Adaptive nonequilibrium design of actin-based metamaterials: Fundamental and practical limits of control.

The adaptive and surprising emergent properties of biological materials self-assembled in far-from-equilibrium environments serve as an inspiration for efforts to design nanomaterials. In particular, controlling the conditions of self-assembly can modulate material properties, but there is no systematic understanding of either how to parameterize external control or how controllable a given material can be. Here, we demonstrate that branched actin networks can be encoded with metamaterial properties by dynamically controlling the applied force under which they grow and that the protocols can be selected using multi-task reinforcement learning. These actin networks have tunable responses over a large dynamic range depending on the chosen external protocol, providing a pathway to encoding "memory" within these structures. Interestingly, we obtain a bound that relates the dissipation rate and the rate of "encoding" that gives insight into the constraints on control-both physical and information theoretical. Taken together, these results emphasize the utility and necessity of nonequilibrium control for designing self-assembled nanostructures.

Toward healthy and sustainable diets for the 21st century: Importance of sociocultural and economic considerations.

Four years after the EAT-Lancet landmark report, worldwide movements call for action to reorient food systems to healthy diets that respect planetary boundaries. Since dietary habits are inherently local and personal, any shift toward healthy and sustainable diets going against this identity will have an uphill road. Therefore, research should address the tension between the local and global nature of the biophysical (health, environment) and social dimensions (culture, economy). Advancing the food system transformation to healthy, sustainable diets transcends the personal control of engaging consumers. The challenge for science is to scale-up, to become more interdisciplinary, and to engage with policymakers and food system actors. This will provide the evidential basis to shift from the current narrative of price, convenience, and taste to one of health, sustainability, and equity. The breaches of planetary boundaries and the environmental and health costs of the food system can no longer be considered externalities. However, conflicting interests and traditions frustrate effective changes in the human-made food system. Public and private stakeholders must embrace social inclusiveness and include the role and accountability of all food system actors from the microlevel to the macrolevel. To achieve this food transformation, a new "social contract," led by governments, is needed to redefine the economic and regulatory power balance between consumers and (inter)national food system actors.

24-Hour Urinary Sodium and Potassium Excretion and Cardiovascular Risk.

BACKGROUND: The relation between sodium intake and cardiovascular disease remains controversial, owing in part to inaccurate assessment of sodium intake. Assessing 24-hour urinary excretion over a period of multiple days is considered to be an accurate method. METHODS: We included individual-participant data from six prospective cohorts of generally healthy adults; sodium and potassium excretion was assessed with the use of at least two 24-hour urine samples per participant. The primary outcome was a cardiovascular event (coronary revascularization or fatal or nonfatal myocardial infarction or stroke). We analyzed each cohort using consistent methods and combined the results using a random-effects meta-analysis. RESULTS: Among 10,709 participants, who had a mean (±SD) age of 51.5±12.6 years and of whom 54.2% were women, 571 cardiovascular events were ascertained during a median study follow-up of 8.8 years (incidence rate, 5.9 per 1000 person-years). The median 24-hour urinary sodium excretion was 3270 mg (10th to 90th percentile, 2099 to 4899). Higher sodium excretion, lower potassium excretion, and a higher sodium-to-potassium ratio were all associated with a higher cardiovascular risk in analyses that were controlled for confounding factors (P≤0.005 for all comparisons). In analyses that compared quartile 4 of the urinary biomarker (highest) with quartile 1 (lowest), the hazard ratios were 1.60 (95% confidence interval [CI], 1.19 to 2.14) for sodium excretion, 0.69 (95% CI, 0.51 to 0.91) for potassium excretion, and 1.62 (95% CI, 1.25 to 2.10) for the sodium-to-potassium ratio. Each daily increment of 1000 mg in sodium excretion was associated with an 18% increase in cardiovascular risk (hazard ratio, 1.18; 95% CI, 1.08 to 1.29), and each daily increment of 1000 mg in potassium excretion was associated with an 18% decrease in risk (hazard ratio, 0.82; 95% CI, 0.72 to 0.94). CONCLUSIONS: Higher sodium and lower potassium intakes, as measured in multiple 24-hour urine samples, were associated in a dose-response manner with a higher cardiovascular risk. These findings may support reducing sodium intake and increasing potassium intake from current levels. (Funded by the American Heart Association and the National Institutes of Health.).

Novel proteomic signatures may indicate MRI-assessed intrahepatic fat state and changes: The DIRECT PLUS clinical trial.

BACKGROUND AND AIMS: We demonstrated in the randomized 18-month DIRECT PLUS trial (n = 294) that a Mediterranean (MED) diet, supplemented with polyphenol-rich Mankai duckweed, green tea, and walnuts and restricted in red/processed meat, caused substantial intrahepatic fat (IHF%) loss compared with 2 other healthy diets, reducing NAFLD by half, regardless of similar weight loss. Here, we investigated the baseline proteomic profile associated with IHF% and the changes in proteomics associated with IHF% changes induced by lifestyle intervention. APPROACH AND RESULTS: We calculated IHF% by proton magnetic resonance spectroscopy (normal IHF% <5% and abnormal IHF% ≥5%). We assayed baseline and 18-month samples for 95 proteomic biomarkers.Participants (age = 51.3 ± 10.8 y; 89% men; and body mass index = 31.3 ± 3.9 kg/m 2 ) had an 89.8% 18-month retention rate; 83% had eligible follow-up proteomics measurements, and 78% had follow-up proton magnetic resonance spectroscopy. At baseline, 39 candidate proteins were significantly associated with IHF% (false discovery rate <0.05), mostly related to immune function pathways (eg, hydroxyacid oxidase 1). An IHF% prediction based on the DIRECT PLUS by combined model ( R2 = 0.47, root mean square error = 1.05) successfully predicted IHF% ( R2 = 0.53) during testing and was stronger than separately inputting proteins/traditional markers ( R2 = 0.43/0.44). The 18-month lifestyle intervention induced changes in 18 of the 39 candidate proteins, which were significantly associated with IHF% change, with proteins related to metabolism, extracellular matrix remodeling, and immune function pathways. Thrombospondin-2 protein change was higher in the green-MED compared to the MED group, beyond weight and IHF% loss ( p = 0.01). Protein principal component analysis revealed differences in the third principal component time distinct interactions across abnormal/normal IHF% trajectory combinations; p < 0.05 for all). CONCLUSIONS: Our findings suggest novel proteomic signatures that may indicate MRI-assessed IHF state and changes during lifestyle intervention. Specifically, carbonic anhydrase 5A, hydroxyacid oxidase 1, and thrombospondin-2 protein changes are independently associated with IHF% change, and thrombospondin-2 protein change is greater in the green-MED/high polyphenols diet.

Metabolomic profiles during early childhood and risk of food allergies and asthma in multiethnic children from a prospective birth cohort.

BACKGROUND: There are increasing numbers of metabolomic studies in food allergy (FA) and asthma, which, however, are predominantly limited by cross-sectional designs, small sample size, and being conducted in European populations. OBJECTIVE: We sought to identify metabolites unique to and shared by children with FA and/or asthma in a racially diverse prospective birth cohort, the Boston Birth Cohort. METHODS: Mass spectrometry-based untargeted metabolomic profiling was performed using venous plasma collected in early childhood (n = 811). FA was diagnosed according to clinical symptoms consistent with an acute hypersensitivity reaction at food ingestion and food specific-IgE > 0.35 kU/L. Asthma was defined on the basis of physician diagnosis. Generalized estimating equations were applied to analyze metabolomic associations with FA and asthma, adjusting for potential confounders. RESULTS: During a mean ± standard deviation follow-up of 11.8 ± 5.2 years from birth, 78 children developed FA and 171 developed asthma. Androgenic and pregnenolone steroids were significantly associated with a lower risk of FA, especially for egg allergy. N,N,N-trimethyl-5-aminovalerate (odds ratio [OR] = 0.65, 95% confidence interval [CI] = 0.48-0.87), and 1-oleoyl-2-arachidonoyl-sn-glycero-3-phosphoinositol (OR = 0.77; 95% CI = 0.66-0.90) were inversely associated with FA risk. Orotidine (OR = 4.73; 95% CI = 2.2-10.2) and 4-cholesten-3-one (OR = 0.52; 95% CI = 0.35-0.77) were the top 2 metabolites associated with risk of asthma, although they had no association with FA. In comparison, children with both FA and asthma exhibited an altered metabolomic profile that aligned with that of FA, including altered levels of lipids and steroids. CONCLUSION: In this US multiethnic prospective birth cohort, unique and shared alterations in plasma metabolites during early childhood were associated with risk of developing FA and/or asthma. These findings await further validation.

The metabolic potential of inflammatory and insulinaemic dietary patterns and risk of type 2 diabetes.

AIMS/HYPOTHESIS: Diets with higher inflammatory and insulinaemic potential have been associated with an increased risk of type 2 diabetes. However, it remains unknown whether plasma metabolomic profiles related to proinflammatory/hyperinsulinaemic diets and to inflammatory/insulin biomarkers are associated with type 2 diabetes risk. METHODS: We analysed 6840 participants from the Nurses' Health Study and Health Professionals Follow-up Study to identify the plasma metabolome related to empirical dietary inflammatory pattern (EDIP), empirical dietary index for hyperinsulinemia (EDIH), four circulating inflammatory biomarkers and C-peptide. Dietary intakes were assessed using validated food frequency questionnaires. Plasma metabolomic profiling was conducted by LC-MS/MS. Metabolomic signatures were derived using elastic net regression. Multivariable Cox regression was used to examine associations of the metabolomic profiles with type 2 diabetes risk. RESULTS: We identified 27 metabolites commonly associated with both EDIP and inflammatory biomarker z score and 21 commonly associated with both EDIH and C-peptide. Higher metabolomic dietary inflammatory potential (MDIP), reflecting higher metabolic potential of both an inflammatory dietary pattern and circulating inflammatory biomarkers, was associated with higher type 2 diabetes risk. The HR comparing highest vs lowest quartiles of MDIP was 3.26 (95% CI 2.39, 4.44). We observed a strong positive association with type 2 diabetes risk for the metabolomic signature associated with EDIP-only (HR 3.75; 95% CI 2.71, 5.17) or inflammatory biomarkers-only (HR 4.07; 95% CI 2.91, 5.69). In addition, higher metabolomic dietary index for hyperinsulinaemia (MDIH), reflecting higher metabolic potential of both an insulinaemic dietary pattern and circulating C-peptide, was associated with greater type 2 diabetes risk (HR 3.00; 95% CI 2.22, 4.06); further associations with type 2 diabetes were HR 2.79 (95% CI 2.07, 3.76) for EDIH-only signature and HR 3.89 (95% CI 2.82, 5.35) for C-peptide-only signature. The diet scores were significantly associated with risk, although adjustment for the corresponding metabolomic signature scores attenuated the associations with type 2 diabetes, these remained significant. CONCLUSIONS/INTERPRETATION: The metabolomic signatures reflecting proinflammatory or hyperinsulinaemic diets and related biomarkers were positively associated with type 2 diabetes risk, supporting that these dietary patterns may influence type 2 diabetes risk via the regulation of metabolism.

Discovery and validation of plasma, saliva and multi-fluid plasma-saliva metabolomic scores predicting insulin resistance and diabetes progression or regression among Puerto Rican adults.

AIMS/HYPOTHESIS: Many studies have examined the relationship between plasma metabolites and type 2 diabetes progression, but few have explored saliva and multi-fluid metabolites. METHODS: We used LC/MS to measure plasma (n=1051) and saliva (n=635) metabolites among Puerto Rican adults from the San Juan Overweight Adults Longitudinal Study. We used elastic net regression to identify plasma, saliva and multi-fluid plasma-saliva metabolomic scores predicting baseline HOMA-IR in a training set (n=509) and validated these scores in a testing set (n=340). We used multivariable Cox proportional hazards models to estimate HRs for the association of baseline metabolomic scores predicting insulin resistance with incident type 2 diabetes (n=54) and prediabetes (characterised by impaired glucose tolerance, impaired fasting glucose and/or high HbA1c) (n=130) at 3 years, along with regression from prediabetes to normoglycaemia (n=122), adjusting for traditional diabetes-related risk factors. RESULTS: Plasma, saliva and multi-fluid plasma-saliva metabolomic scores predicting insulin resistance included highly weighted metabolites from fructose, tyrosine, lipid and amino acid metabolism. Each SD increase in the plasma (HR 1.99 [95% CI 1.18, 3.38]; p=0.01) and multi-fluid (1.80 [1.06, 3.07]; p=0.03) metabolomic scores was associated with higher risk of type 2 diabetes. The saliva metabolomic score was associated with incident prediabetes (1.48 [1.17, 1.86]; p=0.001). All three metabolomic scores were significantly associated with lower likelihood of regressing from prediabetes to normoglycaemia in models adjusting for adiposity (HRs 0.72 for plasma, 0.78 for saliva and 0.72 for multi-fluid), but associations were attenuated when adjusting for lipid and glycaemic measures. CONCLUSIONS/INTERPRETATION: The plasma metabolomic score predicting insulin resistance was more strongly associated with incident type 2 diabetes than the saliva metabolomic score. Only the saliva metabolomic score was associated with incident prediabetes.

Portfolio Diet Score and Risk of Cardiovascular Disease: Findings From 3 Prospective Cohort Studies.

BACKGROUND: The plant-based Portfolio dietary pattern includes recognized cholesterol-lowering foods (ie, plant protein, nuts, viscous fiber, phytosterols, and plant monounsaturated fats) shown to improve several cardiovascular disease (CVD) risk factors in randomized controlled trials. However, there is limited evidence on the role of long-term adherence to the diet and CVD risk. The primary objective was to examine the relationship between the Portfolio Diet Score (PDS) and the risk of total CVD, coronary heart disease (CHD), and stroke. METHODS: We prospectively followed 73 924 women in the Nurses' Health Study (1984-2016), 92 346 women in the Nurses' Health Study II (1991-2017), and 43 970 men in the Health Professionals Follow-up Study (1986-2016) without CVD or cancer at baseline. Diet was assessed using validated food frequency questionnaires at baseline and every 4 years using a PDS that positively ranks plant protein (legumes), nuts and seeds, viscous fiber sources, phytosterols (mg/day), and plant monounsaturated fat sources, and negatively ranks foods high in saturated fat and cholesterol. RESULTS: During up to 30 years of follow-up, 16 917 incident CVD cases, including 10 666 CHD cases and 6473 strokes, were documented. After multivariable adjustment for lifestyle factors and a modified Alternate Healthy Eating Index (excluding overlapping components), comparing the highest with the lowest quintile, participants with a higher PDS had a lower risk of total CVD (pooled hazard ratio [HR], 0.86 [95% CI, 0.81-0.92]; Ptrend<0.001), CHD (pooled HR, 0.86 [95% CI, 0.80-0.93]; Ptrend=0.0001), and stroke (pooled HR, 0.86 [95% CI, 0.78-0.95]; Ptrend=0.0003). In addition, a 25-percentile higher PDS was associated with a lower risk of total CVD (pooled HR, 0.92 [95% CI, 0.89-0.95]), CHD (pooled HR, 0.92 [95% CI, 0.88-0.95]), and stroke (pooled HR, 0.92 [95% CI, 0.87-0.96]). Results remained consistent across sensitivity and most subgroup analyses, and there was no evidence of departure from linearity for CVD, CHD, or stroke. In a subset of participants, a higher PDS was associated with a more favorable blood lipid and inflammatory profile. CONCLUSIONS: The PDS was associated with a lower risk of CVD, including CHD and stroke, and a more favorable blood lipid and inflammatory profile, in 3 large prospective cohorts.

Omega-3 Blood Levels and Stroke Risk: A Pooled and Harmonized Analysis of 183 291 Participants From 29 Prospective Studies.

BACKGROUND: The effect of marine omega-3 PUFAs on risk of stroke remains unclear. METHODS: We investigated the associations between circulating and tissue omega-3 PUFA levels and incident stroke (total, ischemic, and hemorrhagic) in 29 international prospective cohorts. Each site conducted a de novo individual-level analysis using a prespecified analytical protocol with defined exposures, covariates, analytical methods, and outcomes; the harmonized data from the studies were then centrally pooled. Multivariable-adjusted HRs and 95% CIs across omega-3 PUFA quintiles were computed for each stroke outcome. RESULTS: Among 183 291 study participants, there were 10 561 total strokes, 8220 ischemic strokes, and 1142 hemorrhagic strokes recorded over a median of 14.3 years follow-up. For eicosapentaenoic acid, comparing quintile 5 (Q5, highest) with quintile 1 (Q1, lowest), total stroke incidence was 17% lower (HR, 0.83 [CI, 0.76-0.91]; P<0.0001), and ischemic stroke was 18% lower (HR, 0.82 [CI, 0.74-0.91]; P<0.0001). For docosahexaenoic acid, comparing Q5 with Q1, there was a 12% lower incidence of total stroke (HR, 0.88 [CI, 0.81-0.96]; P=0.0001) and a 14% lower incidence of ischemic stroke (HR, 0.86 [CI, 0.78-0.95]; P=0.0001). Neither eicosapentaenoic acid nor docosahexaenoic acid was associated with a risk for hemorrhagic stroke. These associations were not modified by either baseline history of AF or prevalent CVD. CONCLUSIONS: Higher omega-3 PUFA levels are associated with lower risks of total and ischemic stroke but have no association with hemorrhagic stroke.

Metformin and other anti-diabetic medication use and breast cancer incidence in the Nurses' Health Studies.

We aimed to examine the association between the use of metformin and other anti-diabetic medications and breast cancer incidence within two large prospective cohort studies. We followed 185,181 women who participated in the Nurses' Health Study (NHS; 1994-2016) and the NHSII (1995-2017), with baseline corresponding to the date metformin was approved for type 2 diabetes (T2D) treatment in the US Information on T2D diagnosis, anti-diabetes medications, and other covariates was self-reported at baseline and repeatedly assessed by follow-up questionnaires every 2 years. Breast cancer cases were self-reported and confirmed by medical record review. Hazard ratios (HRs) and 95% confidence intervals (CIs) for the association between medication use and breast cancer were estimated using Cox proportional hazards regression models, adjusting for breast cancer risk factors. During 3,324,881 person-years of follow-up, we ascertained 9,192 incident invasive breast cancer cases, of which 451 were among women with T2D. Compared with women without T2D (n = 169,263), neither metformin use (HR = 0.97; 95% CI = 0.81-1.15) nor other anti-diabetic medications use (HR = 1.11; 95% CI = 0.90-1.36) associated with significantly lower breast cancer incidence. Among women with T2D (n = 15,918), compared with metformin never users, metformin ever use was not significantly inversely associated with breast cancer (HR = 0.92; 95% CI = 0.74-1.15). Although we observed that past use of metformin was inversely associated with breast cancer in the T2D population (HR = 0.67; 95% CI = 0.48-0.94), current use (HR = 1.01; 95% CI = 0.80-1.27) and longer duration of metformin use were not associated with breast cancer (each 2-year interval: HR = 1.01; 95% CI = 0.95-1.07). Overall, metformin use was not associated with the risk of developing breast cancer among the overall cohort population or among women with T2D.

Newborn DNA methylation age differentiates long-term weight trajectories: the Boston Birth Cohort.

BACKGROUND: Gestational age (GEAA) estimated by newborn DNA methylation (GAmAge) is associated with maternal prenatal exposures and immediate birth outcomes. However, the association of GAmAge with long-term overweight or obesity (OWO) trajectories is yet to be determined. METHODS: GAmAge was calculated for 831 children from a US predominantly urban, low-income, multi-ethnic birth cohort based on cord blood DNA methylation profile using Illumina EPIC array. Repeated anthropometric measurements aligned with pediatric primary care schedule allowed us to calculate body-mass-index percentiles (BMIPCT) at specific age and to define long-term weight trajectories from birth to 18 years. RESULTS: GAmAge was associated with BMIPCT trajectories, defined by 4 groups: stable (consistent OWO: "early OWO"; constant normal weight: "NW") or non-stable (OWO by year 1 of follow-up: "late OWO"; OWO by year 6 of follow-up: "NW to very late OWO"). GAmAge differentiated between the group with consistently normal BMIPCT pattern and the non-stable groups with late and very late OWO development. Such differentiation was observed in the age periods of birth to 1year, 3years, 6years, 10years, and 14years (p < 0.05 for all). The findings persisted after adjusting for GEAA, maternal smoking, delivery method, and child's sex in multivariate models. Birth weight was a mediator for the GAmAge effect on OWO status for specific groups at multiple age periods. CONCLUSIONS: GAmAge is associated with BMIPCT trajectories from birth to age 18 years, independent of GEAA and birth weight. If further confirmed, GAmAge may serve as an early biomarker for predicting BMI trajectory to inform early risk assessment and prevention of OWO. TRIAL REGISTRATION: ClinicalTrials.gov (NCT03228875).

Diet strategies for promoting healthy aging and longevity: An epidemiological perspective.

In recent decades, global life expectancies have risen significantly, accompanied by a marked increase in chronic diseases and population aging. This narrative review aims to summarize recent findings on the dietary factors influencing chronic diseases and longevity, primarily from large cohort studies. First, maintaining a healthy weight throughout life is pivotal for healthy aging and longevity, mirroring the benefits of lifelong, moderate calorie restriction in today's obesogenic food environment. Second, the specific types or food sources of dietary fat, protein, and carbohydrates are more important in influencing chronic disease risk and mortality than their quantity. Third, some traditional diets (e.g., the Mediterranean, Nordic, and Okinawa) and contemporary dietary patterns, such as healthy plant-based diet index, the DASH (dietary approaches to stop hypertension) diet, and alternate healthy eating index, have been associated with lower mortality and healthy longevity. These patterns share many common components (e.g., a predominance of nutrient-rich plant foods; limited red and processed meats; culinary herbs and spices prevalent in global cuisines) while embracing distinct elements from different cultures. Fourth, combining a healthy diet with other lifestyle factors could extend disease-free life expectancies by 8-10 years. While adhering to core principles of healthy diets, it is crucial to adapt dietary recommendations to individual preferences and cultures as well as nutritional needs of aging populations. Public health strategies should aim to create a healthier food environment where nutritious options are readily accessible, especially in public institutions and care facilities for the elderly. Although further mechanistic studies and human trials are needed to better understand molecular effects of diet on aging, there is a pressing need to establish and maintain long-term cohorts studying diet and aging in culturally diverse populations.

All-cause and cause-specific mortality risk and loss in life expectancy associated with incident type 2 diabetes onset age and duration.

BACKGROUND: Evidence on type 2 diabetes onset age and duration on mortality risk has been limited by short follow-up, inadequate control for confounding, missing repeated measurements, and inability to cover the full range of onset age, duration, and major causes of death. Moreover, scarce data dissect how type 2 diabetes onset age and duration shape life expectancy. METHODS: We evaluate prospectively these topics based on 270,075 eligible participants in the Nurses' Health Studies and Health Professionals Follow-up Study, leveraging repeated measurements throughout up to 40 years of follow-up. Cox models were used to estimate hazard ratios (HRs) and 95% confidence intervals (CIs). RESULTS: In fully adjusted analyses, incident early onset type 2 diabetes (diagnosed <40 years of age) was associated with significantly higher mortality from all-causes (HR, 95% CI was 3.16, 2.64-3.79; vs. individuals without type 2 diabetes), cardiovascular disease (6.56, 4.27-10.1), respiratory disease (3.43, 1.38-8.51), neurodegenerative disease (5.13, 2.09-12.6), and kidney disease (8.55, 1.98-36.9). The relative risk elevations declined dramatically with each higher decade of age at diagnosis for deaths from most of these causes, though the absolute risk difference increased continuously. A substantially higher cumulative incidence of mortality and a greater loss in life expectancy were associated with younger age at type 2 diabetes diagnosis. Longer disease duration was associated with generally higher relative and absolute risk of mortality. CONCLUSION: Early onset of type 2 diabetes and longer disease duration are associated with substantially increased risk of all-cause and cause-specific mortality and greater loss in life expectancy.

Plasma metabolite profile of legume consumption and future risk of type 2 diabetes and cardiovascular disease.

BACKGROUND: Legume consumption has been linked to a reduced risk of type 2 diabetes (T2D) and cardiovascular disease (CVD), while the potential association between plasma metabolites associated with legume consumption and the risk of cardiometabolic diseases has never been explored. Therefore, we aimed to identify a metabolite signature of legume consumption, and subsequently investigate its potential association with the incidence of T2D and CVD. METHODS: The current cross-sectional and longitudinal analysis was conducted in 1833 PREDIMED study participants (mean age 67 years, 57.6% women) with available baseline metabolomic data. A subset of these participants with 1-year follow-up metabolomics data (n = 1522) was used for internal validation. Plasma metabolites were assessed through liquid chromatography-tandem mass spectrometry. Cross-sectional associations between 382 different known metabolites and legume consumption were performed using elastic net regression. Associations between the identified metabolite profile and incident T2D and CVD were estimated using multivariable Cox regression models. RESULTS: Specific metabolic signatures of legume consumption were identified, these included amino acids, cortisol, and various classes of lipid metabolites including diacylglycerols, triacylglycerols, plasmalogens, sphingomyelins and other metabolites. Among these identified metabolites, 22 were negatively and 18 were positively associated with legume consumption. After adjustment for recognized risk factors and legume consumption, the identified legume metabolite profile was inversely associated with T2D incidence (hazard ratio (HR) per 1 SD: 0.75, 95% CI 0.61-0.94; p = 0.017), but not with CVD incidence risk (1.01, 95% CI 0.86-1.19; p = 0.817) over the follow-up period. CONCLUSIONS: This study identified a set of 40 metabolites associated with legume consumption and with a reduced risk of T2D development in a Mediterranean population at high risk of cardiovascular disease. TRIAL REGISTRATION: ISRCTN35739639.

Type 2 diabetes metabolomics score and risk of progression to type 2 diabetes among women with a history of gestational diabetes mellitus.

BACKGROUND: Several metabolites are individually related to incident type 2 diabetes (T2D) risk. We prospectively evaluated a novel T2D-metabolite pattern with a risk of progression to T2D among high-risk women with a history of gestational diabetes mellitus (GDM). METHODS: The longitudinal Nurses' Health Study II cohort enroled 116,429 women in 1989 and collected blood samples from 1996 to 1999. We profiled plasma metabolites in 175 incident T2D cases and 175 age-matched controls, all with a history of GDM before the blood draw. We derived a metabolomics score from 21 metabolites previously associated with incident T2D in the published literature by scoring according to the participants' quintile (1-5 points) of each metabolite. We modelled the T2D metabolomics score categorically in quartiles and continuously per 1 standard deviation (SD) with the risk of incident T2D using conditional logistic regression models adjusting for body mass index at the blood draw, and other established T2D risk factors. RESULTS: The percentage of women progressing to T2D ranged from 10% in the bottom T2D metabolomics score quartile to 78% in the highest score quartile. Adjusting for established T2D risk factors, women in the highest quartile had more than a 20-fold greater diabetes risk than women in the lowest quartile (odds ratios [OR] = 23.1 [95% CI = 8.6, 62.1]; p for trend<0.001). The continuous T2D metabolomics score was strongly and positively associated with incident T2D (adjusted OR = 2.7 per SD [95% CI = 1.9, 3.7], p < 0.0001). CONCLUSIONS: A pattern of plasma metabolites among high-risk women is associated with a markedly elevated risk of progression to T2D later in life.

Red Meat Intake and the Risk of Cardiovascular Diseases: A Prospective Cohort Study in the Million Veteran Program.

BACKGROUND: Red meat consumption was associated with an increased risk of cardiovascular disease (CVD) in prospective cohort studies and a profile of biomarkers favoring high CVD risk in short-term controlled trials. However, several recent systematic reviews and meta-analyses concluded with no or weak evidence for limiting red meat intake. OBJECTIVES: To prospectively examine the associations between red meat intake and incident CVD in an ongoing cohort study with diverse socioeconomic and racial or ethnic backgrounds. METHODS: Our study included 148,506 participants [17,804 female (12.0%)] who were free of cancer, diabetes, and CVD at baseline from the Million Veteran Program. A food frequency questionnaire measured red meat intakes at baseline. Nonfatal myocardial infarction and acute ischemic stroke were identified through a high-throughput phenotyping algorithm, and fatal CVD events were identified by searching the National Death Index. RESULTS: Comparing the extreme categories of intake, the multivariate-adjusted relative risks of CVD was 1.18 (95% CI: 1.01, 1.38; P-trend < 0.0001) for total red meat, 1.14 (95% CI: 0.96, 1.36; P-trend = 0.01) for unprocessed red meat, and 1.29 (95% CI: 1.04, 1.60; P-trend = 0.003) for processed red meat. We observed a more pronounced positive association between red meat intake and CVD in African American participants than in White participants (P-interaction = 0.01). Replacing 0.5 servings/d of red meat with 0.5 servings/d of nuts, whole grains, and skimmed milk was associated with 14% (RR: 0.86; 95% CI: 0.83, 0.90), 7% (RR: 0.93; 95% CI: 0.89, 0.96), and 4% (RR: 0.96; 95% CI: 0.94, 0.99) lower risks of CVD, respectively. CONCLUSIONS: Red meat consumption is associated with an increased risk of CVD. Our findings support lowering red meat intake and replacing red meat with plant-based protein sources or low-fat dairy foods as a key dietary recommendation for the prevention of CVD.

The effect of Mankai plant consumption on postprandial glycaemic response among patients with type 2 diabetes: A randomized crossover trial.

AIM: To explore the effect of Mankai, a cultivated aquatic duckweed green plant, on postprandial glucose (PG) excursions in type 2 diabetes (T2D). METHODS: In a 4-week, randomized crossover-controlled trial, we enrolled 45 adults with T2D (HbA1c range: 6.5%-8.5%) from two sites in Israel. Participants were randomized to drink Mankai (200 mL of raw-fresh-aquatic plant + 100 mL of water, 40 kcal, ~10 g of dry matter equivalent) or water (300 mL) following dinner, for 2 weeks each, with a 4-day washout interval, without dietary, physical activity or pharmacotherapy alterations. We used continuous glucose monitoring (CGM) devices. RESULTS: Forty patients (adherence rate = 88.5%; 743 person-intervention-days, 68.9% men, age = 64 years, HbA1c = 6.8%) completed the study with a consistent diet and complete CGM reads. Only two-thirds of the individuals responded beneficially to Mankai. Overall, Mankai significantly lowered the PG peak by 19.3% (∆peak = 24.3 ± 16.8 vs. 30.1 ± 18.5 mg/dL; P < .001) and delayed the time-to-peak by 20.0% (112.5 [interquartile range: 75-135] vs. 90 [60-105] min; P < .001) compared with water. The PG incline and decline slopes were shallower following postdinner Mankai (incline slope: 16.8 vs. water: 29.9 mg/[dL h]; P < .001; decline slope: -6.1 vs. water: -7.9 mg/[dL h]; P < .01). Mean postprandial net incremental area-under-the-glucose-curve was lowered by 20.1% with Mankai compared with water (P = .03). Results were consistent across several sensitivity and subgroup analyses, including across antidiabetic pharmacotherapy treatment groups. Within 2 weeks, the triglycerides/high-density lipoprotein cholesterol ratio in the Mankai group (-0.5 ± 1.3) decreased versus water (+0.3 ± 1.5, P = .05). CONCLUSIONS: Mankai consumption may mitigate the PG response in people with T2D with an ~20% improvement in glycaemic values. These findings provide case-study evidence for plant-based treatments in T2D to complement a healthy lifestyle and pharmacotherapy.

The MIND diet, brain transcriptomic alterations, and dementia.

INTRODUCTION: Dietary patterns are associated with dementia risk, but the underlying molecular mechanisms are largely unknown. METHODS: We used RNA sequencing data from post mortem prefrontal cortex tissue and annual cognitive evaluations from 1204 participants in the Religious Orders Study and Memory and Aging Project. We identified a transcriptomic profile correlated with the MIND diet (Mediterranean-Dietary Approaches to Stop Hypertension Intervention for Neurodegenerative Delay) among 482 individuals who completed ante mortem food frequency questionnaires; and examined its associations with cognitive health in the remaining 722 participants. RESULTS: We identified a transcriptomic profile, consisting of 50 genes, correlated with the MIND diet score (p = 0.001). Each standard deviation increase in the transcriptomic profile score was associated with a slower annual rate of decline in global cognition (ß = 0.011, p = 0.003) and lower odds of dementia (odds ratio = 0.76, p = 0.0002). Expressions of several genes (including TCIM and IGSF5) appeared to mediate the association between MIND diet and dementia. DISCUSSION: A brain transcriptomic profile for healthy diets revealed novel genes potentially associated with cognitive health. HIGHLIGHTS: Why healthy dietary patterns are associated with lower dementia risk are unknown. We integrated dietary, brain transcriptomic, and cognitive data in older adults. Mediterranean-Dietary Approaches to Stop Hypertension Intervention for Neurodegenerative Delay (MIND) diet intake is correlated with a specific brain transcriptomic profile. This brain transcriptomic profile score is associated with better cognitive health. More data are needed to elucidate the causality and functionality of identified genes.

Interplay between diet, circulating indolepropionate concentrations and cardiometabolic health in US populations.

OBJECTIVES: To identify indolepropionate (IPA)-predicting gut microbiota species, investigate potential diet-microbiota interactions, and examine the prospective associations of circulating IPA concentrations with type 2 diabetes (T2D) and coronary heart disease (CHD) risk in free-living individuals. DESIGN: We included 287 men from the Men's Lifestyle Validation Study, a substudy of the Health Professionals Follow-Up Study (HPFS), who provided up to two pairs of faecal samples and two blood samples. Diet was assessed using 7-day diet records. Associations between plasma concentrations of tryptophan metabolites and T2D CHD risk were examined in 13 032 participants from Nurses' Health Study (NHS), NHSII and HPFS. RESULTS: We identified 17 microbial species whose abundance was significantly associated with plasma IPA concentrations. A significant association between higher tryptophan intake and higher IPA concentrations was only observed among men who had higher fibre intake and a higher microbial species score consisting of the 17 species (p-interaction<0.01). Dietary and plasma concentrations of tryptophan and most kynurenine pathway metabolites were positively associated with T2D risk (HRQ5 vs Q1 ranged from 1.17 to 1.46) while a significant inverse association was found for IPA (HRQ5 vs Q1 (95% CI) 0.70 (0.56 to 0.88)). No associations were found in CHD for any plasma tryptophan metabolites. CONCLUSIONS: Specific microbial species and dietary fibre jointly predicted significantly higher circulating IPA concentrations at higher tryptophan intake. Dietary and plasma tryptophan, as well as its kynurenine pathway metabolites, demonstrated divergent associations from those for IPA, which was significantly predictive of lower risk of T2D.

The effect of polyphenols on DNA methylation-assessed biological age attenuation: the DIRECT PLUS randomized controlled trial.

BACKGROUND: Epigenetic age is an estimator of biological age based on DNA methylation; its discrepancy from chronologic age warrants further investigation. We recently reported that greater polyphenol intake benefitted ectopic fats, brain function, and gut microbiota profile, corresponding with elevated urine polyphenols. The effect of polyphenol-rich dietary interventions on biological aging is yet to be determined. METHODS: We calculated different biological aging epigenetic clocks of different generations (Horvath2013, Hannum2013, Li2018, Horvath skin and blood2018, PhenoAge2018, PCGrimAge2022), their corresponding age and intrinsic age accelerations, and DunedinPACE, all based on DNA methylation (Illumina EPIC array; pre-specified secondary outcome) for 256 participants with abdominal obesity or dyslipidemia, before and after the 18-month DIRECT PLUS randomized controlled trial. Three interventions were assigned: healthy dietary guidelines, a Mediterranean (MED) diet, and a polyphenol-rich, low-red/processed meat Green-MED diet. Both MED groups consumed 28 g walnuts/day (+ 440 mg/day polyphenols). The Green-MED group consumed green tea (3-4 cups/day) and Mankai (Wolffia globosa strain) 500-ml green shake (+ 800 mg/day polyphenols). Adherence to the Green-MED diet was assessed by questionnaire and urine polyphenols metabolomics (high-performance liquid chromatography quadrupole time of flight). RESULTS: Baseline chronological age (51.3 ± 10.6 years) was significantly correlated with all methylation age (mAge) clocks with correlations ranging from 0.83 to 0.95; p < 2.2e - 16 for all. While all interventions did not differ in terms of changes between mAge clocks, greater Green-Med diet adherence was associated with a lower 18-month relative change (i.e., greater mAge attenuation) in Li and Hannum mAge (beta = - 0.41, p = 0.004 and beta = - 0.38, p = 0.03, respectively; multivariate models). Greater Li mAge attenuation (multivariate models adjusted for age, sex, baseline mAge, and weight loss) was mostly affected by higher intake of Mankai (beta = - 1.8; p = 0.061) and green tea (beta = - 1.57; p = 0.0016) and corresponded with elevated urine polyphenols: hydroxytyrosol, tyrosol, and urolithin C (p < 0.05 for all) and urolithin A (p = 0.08), highly common in green plants. Overall, participants undergoing either MED-style diet had ~ 8.9 months favorable difference between the observed and expected Li mAge at the end of the intervention (p = 0.02). CONCLUSIONS: This study showed that MED and green-MED diets with increased polyphenols intake, such as green tea and Mankai, are inversely associated with biological aging. To the best of our knowledge, this is the first clinical trial to indicate a potential link between polyphenol intake, urine polyphenols, and biological aging. TRIAL REGISTRATION: ClinicalTrials.gov, NCT03020186.