Importance:Higher coffee intake has been associated with lower risk of type 2 diabetes (T2D), but the underlying biological pathways remain incompletely understood. Objective:To examine associations of coffee intake with insulin sensitivity, adiposity, and T2D risk, and assess whether coffee intake modifies associations between pathway-specific genetic susceptibility and incident T2D. Design Setting and Participants:Cross-sectional analyses among 806 participants without T2D in the VITamin D and OmegA-3 TriaL (VITAL) clinical sub-cohort, who underwent repeated dietary assessment, clinical phenotyping, and dual-energy X-ray absorptiometry imaging at baseline and year-2. Prospective analyses among 333,053 UK Biobank participants without T2D at baseline who had dietary and genetic data and were followed for a median of 13.3 years. Exposures:Coffee intake assessed by food frequency questionnaires. In UK Biobank, 12 pathway-specific polygenic scores (pPS) representing distinct T2D pathophysiological mechanisms were evaluated. Main Outcomes and Measures:The primary outcomes, in VITAL, were HbA1c, oral glucose tolerance test-derived measures of glucose response and insulin sensitivity, β-cell function, and overall, truncal, and visceral adiposity; in UK Biobank, was incident T2D. Results:In VITAL, higher coffee intake was associated with higher insulin sensitivity (standardized β per cup/day, 0.046; P = .004) and lower visceral adipose tissue mass (β, -0.047; P = .006), after adjusting for demographic, lifestyle, and clinical factors, including body mass index. In UK Biobank, higher coffee intake was associated with lower T2D incidence (hazard ratio per cup/day, 0.96; 95% CI, 0.95-0.97), lower triglyceride-to-HDL cholesterol ratio (β,-0.01; P = 2.51 × 10^-19), and lower visceral adipose tissue mass (β, -0.01; P = 4.28 × 10^-9). Associations of 3 pPS related to insulin resistance and fat distribution with incident T2D were attenuated among participants consuming higher amount of coffee than among non-consumers (P for interaction < .0043). Conclusions and Relevance:Higher coffee intake was associated with greater insulin sensitivity, lower visceral adiposity, and lower risk of T2D. Together with the attenuation of associations between pathway-specific genetic susceptibility and T2D risk among higher coffee consumers, these findings suggest that insulin resistance and visceral adiposity-related pathways may contribute to the association between coffee intake and T2D risk. Key Points:Question: Is coffee intake associated with specific insulin sensitivity and adiposity markers, and type 2 diabetes risk, and does it modify associations between pathway-specific genetic susceptibility and type 2 diabetes?Findings: In analyses repeated dietary, clinical, and imaging phenotyping in 806 VITAL participants and prospective data from 333,053 UK Biobank participants, higher coffee intake was associated with greater insulin sensitivity, lower visceral adiposity, and lower type 2 diabetes risk. Higher coffee intake also attenuated associations of three pathway-specific polygenic scores related to insulin resistance and fat distribution with type 2 diabetes risk.Meaning: These findings suggest that pathways related to insulin sensitivity and visceral adiposity may contribute to the associations between coffee intake and lower type 2 diabetes risk.

The human metabolome reflects complex metabolic states affected by genetic and environmental factors. However, metabolites associated with type 2 diabetes (T2D) risk and their determinants remain insufficiently characterized. Here we integrated blood metabolomic, genomic and lifestyle data from up to 23,634 initially T2D-free participants from ten cohorts. Of 469 metabolites examined, 235 were associated with incident T2D during up to 26 years of follow-up, including 67 associations not previously reported across bile acid, lipid, carnitine, urea cycle and arginine/proline, glycine and histidine pathways. Further genetic analyses linked these metabolites to signaling pathways and clinical traits central to T2D pathophysiology, including insulin resistance, glucose/insulin response, ectopic fat deposition, energy/lipid regulation and liver function. Lifestyle factors-particularly physical activity, obesity and diet-explained greater variations in T2D-associated versus non-associated metabolites, with specific metabolites revealed as potential mediators. Finally, a 44-metabolite signature improved T2D risk prediction beyond conventional factors. These findings provide a foundation for understanding T2D mechanisms and may inform precision prevention targeting specific metabolic pathways.

Importance:Weight gain is common during menopause, and healthy dietary patterns are key to its management. However, effectiveness of different diets for weight management during this period remains unclear. Objective:To examine and compare associations of multiple dietary patterns with weight gain and obesity risk in the years surrounding menopause. Design, Setting, and Participants:This prospective, population-based cohort study included women observed over a 12-year period surrounding menopause in the Nurses' Health Study II (1989-2019). Data analysis was performed between November 2024 and May 2025. Exposures:Diet was assessed every 4 years using validated food frequency questionnaires. Dietary scores included the plant-based diet index (PDI), healthy PDI, unhealthy PDI, Mediterranean diet, Dietary Approaches to Stop Hypertension, Planetary Health Diet Index (PHDI), low-carbohydrate diet (LCD), healthy LCD, unhealthy LCD, empirical dietary inflammatory pattern, empirical dietary index for hyperinsulinemia (EDIH), and ultraprocessed food intake. Main Outcomes and Measures:The outcomes were annual changes in self-reported body weight (kilograms per year) and incident obesity. Generalized estimating equations were used to estimate annual weight change across dietary patterns. Cox proportional hazards models were used to estimate risk of obesity across dietary patterns. Results:Among 38 283 women (mean [SD] age, 45.6 [3.0] years), the mean (SD) weight gain was 0.80 (1.00) kg per year. During 340 122 person-years of follow-up, 5214 women developed obesity. After adjusting for age, race and ethnicity, marital status, income, postmenopausal hormone therapy use, parity, smoking, alcohol, energy intake, physical activity, and baseline body mass index, the reverse EDIH (quintile 5 vs 1) was associated with the largest reduction in weight gain (mean, -0.28 kg/y; 95% CI, -0.30 to -0.26 kg/y). For incident obesity, the lowest risk was observed for the PHDI (hazard ratio, 0.46; 95% CI, 0.42 to 0.51) and reverse EDIH (hazard ratio, 0.51; 95% CI, 0.46 to 0.56). EDIH showed the largest positive correlations with red or processed meats, sodium, and French fries. PHDI showed the largest positive correlations with nuts, unsaturated fats, whole grain carbohydrates, and vegetable protein. Conclusions and Relevance:In this prospective cohort study of women during menopause, adopting low-insulinemic and planetary health diets, low in red and processed meats, sodium, potatoes, and French fries and rich in nuts, legumes, fruits, vegetables, and whole grains, was associated with optimized weight management.

Poor diet quality is strongly associated with elevated cardiovascular disease morbidity and mortality risk. This American Heart Association scientific statement for food-based cardiovascular health optimization and cardiovascular disease risk reduction guidance summarizes available evidence and provides contextual guidance for the key features of heart-healthy dietary patterns. It enumerates collateral benefits of adopting a heart-healthy dietary pattern in terms of nutrient intake adequacy and compatibility with other chronic disease risk reduction guidance. The features of a heart-healthy dietary pattern include (1) adjusting energy intake and expenditure to achieve and maintain a healthy body weight; (2) eating plenty of vegetables and fruits and choosing a wide variety; (3) choosing foods made mostly with whole grains rather than refined grains; (4) choosing healthy sources of protein; (5) choosing sources of unsaturated fats in place of sources of saturated fat; (6) choosing minimally processed foods instead of ultraprocessed foods; (7) minimizing intake of added sugars in beverages and foods; (8) reducing sodium intake by choosing foods low in sodium and preparing foods with minimal or no salt; and (9) if alcohol is not consumed, do not start; if alcohol is consumed, limit intake.

OBJECTIVE:This study aimed to identify metabolomic profiles associated with type 2 diabetes and insulin resistance (HOMA-IR) and relate them to the risk of total mortality. METHODS:A longitudinal study was conducted in a subset of participants from a diabetes case-cohort study (mean age, 66.5 years; 62% women; 176/699 with incident T2D) within the PREDIMED trial. Plasma metabolites were analyzed using LC-MS/MS methods at baseline (discovery sample) and 1-year follow-up (validation sample). Multi-metabolite profile scores for type 2 diabetes and HOMA-IR, respectively, were derived using elastic net regression. Cox proportional hazards were fitted to assess the association between metabolomic profiles and total mortality, adjusting for potential confounders. External validation was performed in the NHS/HPFS cohorts. RESULTS:A total of 31 metabolites were associated with type 2 diabetes and 105 with HOMA-IR. Both metabolomic profiles were significantly associated with a higher risk of total mortality (type 2 diabetes HR = 1.52, 95%CI: 1.04-2.25; HOMA-IR HR = 1.33, 95%CI: 1.00-1.75) in the PREDIMED cohort. Shared metabolites between both metabolomic signatures, including glycine, SDMA, DMGV, and phosphocreatine, were associated with mortality. These associations were replicated in a pooled analysis of three independent American cohorts (type 2 diabetes HR = 1.09, 95%CI: 1.05-1.13; HOMA-IR HR = 1.04, 95%CI: 1.00-1.09). CONCLUSIONS:In an older population at high cardiometabolic risk, metabolomic scores of type 2 diabetes and insulin resistance were associated with total mortality risk, potentially explaining some mechanisms behind the increased risk of mortality observed in epidemiological studies for individuals with glycemic dysregulations.

BACKGROUND:Previous cohort studies of physical activity and cognitive health have often been limited by small sample sizes, short follow-up durations, absence of long-term assessments of physical activity, and potential reverse causation. We aimed to prospectively examine the associations between long-term physical activity and multiple cognitive outcomes. METHODS:In this study, we used data from two ongoing US prospective cohorts: the Nurses' Health Study (established in 1976, comprising 121 700 female registered nurses aged 30-55 years at enrolment) and the Health Professionals Follow-Up Study (HPFS; established in 1986, comprising 51 492 male health professionals aged 40-75 years at enrolment). Discretionary physical activity was assessed approximately every 2-4 years using self-report questionnaires, beginning in 1986 for both cohorts. Total physical activity, walking, and vigorous aerobic exercise were each expressed as the summed metabolic equivalent of task hours per week. We ascertained incident dementia cases (a composite endpoint of self-reported physician-diagnosed dementia and deaths due to dementia) in eligible Nurses' Health Study participants (1990-2023) and HPFS participants (1990-2023); deaths due to dementia were confirmed using medical records, death certificates, and autopsy reports. Objective cognitive function was assessed in Nurses' Health Study participants only (1995-2008) using the Telephone Interview for Cognitive Status (TICS). Subjective cognitive decline was self-reported by Nurses' Health Study participants (followed up in 2012 and 2014) and HPFS participants (followed up in 2008, 2012, 2016, 2018, and 2020) via questionnaires with binary questions that assessed subjective cognitive concerns across multiple domains. Participants were excluded from the analysis if they had dementia, stroke, cancer, were missing total physical activity or walking data, or reported difficulties with walking at baseline. Outcomes were analysed using multivariable-adjusted regression models. We used a 4-year lag approach in our main analyses to minimise the potential for reverse causation. FINDINGS:Our final samples comprised 63 596 Nurses' Health Study participants and 43 440 HPFS participants for the dementia endpoints, 13 647 Nurses' Health Study participants for assessing objective cognitive function, and 29 801 Nurses' Health Study participants and 17 162 HPFS participants for assessing subjective cognitive decline. Compared with participants in the lowest quartile for total physical activity, those in the highest quartile had a lower risk of dementia (hazard ratio [HR] 0·72, 95% CI 0·68-0·76; p<0·0001 for trend) and subjective cognitive decline (relative risk [RR] 0·77, 95% CI 0·73-0·80; p<0·0001 for trend). Being in the highest versus the lowest tertile for walking or vigorous aerobic exercise was also associated with lower risk for dementia (HR 0·76, 95% CI 0·72-0·80 for walking and 0·89, 0·85-0·93 for vigorous aerobic exercise; p<0·0001 for trend for both activities) and subjective cognitive decline (RR 0·82, 95% CI 0·79-0·86 for walking and 0·89, 0·86-0·93 for vigorous aerobic exercise; p<0·0001 for trend for both activities). Additionally, being in the highest quartile of total physical activity versus the lowest quartile was associated with fewer years of age-related cognitive differences in global cognition (mean difference -1·15, 95% CI -1·69 to -0·60; p<0·0001 for trend), verbal memory (-1·27, -1·86 to -0·68; p<0·0001 for trend), and TICS score (-0·79, -1·36 to -0·23; p=0·016 for trend). Similar decreases were observed for vigorous aerobic exercise but not for walking. INTERPRETATION:Higher levels of physical activity were associated with a lower risk of dementia and better cognitive performance. These findings support physical activity as a potential strategy to promote long-term cognitive health. FUNDING:US National Institutes of Health.

Objective To examine the associations of long term engagement in individual physical activities and physical activity variety with the risk of death.Design Prospective cohort studies.Setting Nurses' Health Study (1986-2018) and Health Professionals Follow-Up Study (1986-2020).Participants 70 725 women and 40 742 men who were free of diabetes, cardiovascular disease, cancer, respiratory disease, or neurological disease and had complete physical activity information at baseline (leisure time physical activity was biennially updated using validated questionnaires during follow-up; the variety of physical activity was measured as the total number of individual physical activities in which participants consistently engaged).Main outcome measures All cause and cause specific mortality.Results During 2 431 318 person years of follow-up, 38 847 deaths were recorded, with 9901 from cardiovascular disease, 10 719 from cancer, and 3159 from respiratory disease. Total physical activity and most individual physical activities, except for swimming, were associated with lower mortality with non-linear dose-response relations. The pooled multivariable adjusted hazard ratios for all cause mortality in the highest categories of physical activity levels, compared with the lowest, were 0.83 (95% confidence interval 0.80 to 0.85) for walking, 0.89 (0.85 to 0.94) for jogging, 0.87 (0.80 to 0.93) for running, 0.96 (0.93 to 0.99) for bicycling, 1.01 (0.97 to 1.05) for swimming, 0.85 (0.80 to 0.89) for tennis or squash, 0.90 (0.87 to 0.93) for climbing stairs, 0.86 (0.84 to 0.89) for rowing or callisthenics, and 0.87 (0.82 to 0.91) for weight training or resistance exercises. Higher physical activity variety was associated with lower mortality. After adjustment for total physical activity levels, participants in the group with the highest physical activity variety score (group 5), compared with those in the lowest group (group 1), had a 19% lower all cause mortality and 13-41% lower mortality from cardiovascular disease, cancer, respiratory disease, and other causes (all P for trend <0.001).Conclusions Habitual engagement in most types of physical activity was associated with lower mortality. The variety of physical activity was inversely associated with mortality, independent of total physical activity levels. Overall, these data support the notion that long term engagement in multiple types of physical activity may help extend the lifespan.

Background Low-carbohydrate diet (LCD) and low-fat diet (LFD) patterns are practiced by many in the United States, although their health effects, as well as the role of diet quality in the effects, are not fully understood. Objectives This study aimed to prospectively examine the associations of these diets, which emphasize different quantities and qualities of macronutrients, as well as their objective metabolomic indices, with coronary heart disease (CHD) risk in U.S. individuals. Methods We followed 42,720 men in the Health Professionals Follow-Up Study (HPFS) (1986-2016), 64,164 women in the Nurses’ Health Study (NHS) (1986-2018), and 91,589 women in NHSII (1991-2019) for CHD incidence. Five LCD and 5 LFD indices were derived based on food frequency questionnaire (FFQ) assessments, each emphasizing different sources and qualities of macronutrients (animal products vs plant-based foods, whole grains vs refined carbohydrates, etc). Multimetabolite scores of LCD and LFD indices assessed using FFQ assessments were developed through elastic net regressions among 1,146 healthy participants in the lifestyle validation studies (LVS), substudies embedded in the NHS/NHSII/HPFS. Results During 5,248,916 person-years of follow-up, we documented 20,033 CHD cases. When comparing individuals with the highest LCD scores (emphasizing lower carbohydrate contents) and those with the lowest, the pooled multivariable-adjusted hazard ratios (95% CIs) for CHD were 1.05 (1.01-1.10) for overall LCD, 1.07 (1.02-1.12) for animal LCD, 0.94 (0.90-0.99) for vegetable LCD, 1.14 (1.09-1.20) for unhealthy LCD, and 0.85 (0.82-0.89) for healthy LCD. These estimates were 0.93 (0.89-0.98) for overall LFD, 0.94 (0.90-0.98) for animal LFD, 0.87 (0.83-0.91) for vegetable LFD, 1.12 (1.07-1.17) for unhealthy LFD, and 0.87 (0.83-0.91) for healthy LFD. The healthy versions of the LCD and LFD patterns were also linked to lower triglycerides, higher high-density lipoprotein cholesterol, and lower high-sensitivity C-reactive protein levels, as well as favorable metabolomic profiles, including increased 3-indolepropionic acid and decreased valine. Unhealthy patterns showed opposite associations. Multimetabolite scores of LCD and LFD indices were developed in the LVS (Spearman r = 0.57-0.68) and replicated in NHS, NHSII, and HPFS (r = 0.21-0.38). They showed associations with CHD risk highly consistent with those based on FFQ assessments. Conclusions These findings highlight the critical role of diet quality in determining health effects of low-carbohydrate and low-fat diets on CHD risk. The healthy versions of these diets may exert their health benefits through some common pathways that together entail favorable cardiovascular risk profile and lower CHD risk.

Background Asian American (AsA) and Native Hawaiian and Pacific Islander (NHPI) populations are underrepresented in U.S. health studies. Objectives The MOSAAIC (Multi-ethnic Observational Study in American Asian and Pacific Islander Communities) is a cohort study designed to improve understanding of disparities in cardiovascular disease and other health conditions affecting AsA and NHPI groups. Methods Through broad eligibility criteria and outreach tailored to each study community, MOSAAIC will include 11,500 adults aged 18+ years living in 5 field center regions: New York, Philadelphia, Chicago, San Francisco Bay Area, and Honolulu. The protocol specifies sample-size targets to allow valid comparisons among persons having personal or family origins in 4 geographically defined regions, including East Asia (the largest groups being Chinese and Korean), South Asia (Indian), Southeast Asia (Vietnamese and Filipino) and Oceania (NHPI). Measurements to be obtained at an in-person examination include clinical laboratory tests, medical history, medication use, spirometry, cognitive and physical function, anthropometry, and electrocardiogram. Surveys in multiple languages to assess medical, behavioral, lifestyle, social and environmental influences on health were developed by a multistep process to ensure equivalency between translations and cultural appropriateness. Biospecimens are stored for future studies. Long-term follow-up will be conducted to ascertain and adjudicate major health events including myocardial infarction, stroke, heart failure, and mortality. Conclusions The National Institutes of Health established MOSAAIC as a resource for wide-ranging epidemiologic investigation of factors related to cardiometabolic, pulmonary, or mental health in persons of diverse AsA and NHPI background.

BACKGROUND:Type 2 diabetes (T2D) is associated with an increased risk of premature death. Diet may influence long-term health outcomes among individuals with T2D, but prospective evidence on dietary patterns and mortality remains limited. OBJECTIVES:To prospectively examine associations of eleven pre-defined or empirically-developed dietary patterns with all-cause and cause-specific mortality (e.g., cardiovascular disease [CVD] and cancer) among U.S. individuals with T2D. METHODS:We included 7,795 participants with incident T2D in the Nurses' Health Study (1984-2016) and Health Professionals Follow-Up Study (1986-2020), who were free of CVD and cancer at diagnosis. Diet was assessed using a validated food frequency questionnaire and updated every four years. Cox proportional hazards models were used to estimate hazard ratios (HRs) and 95% CIs. RESULTS:Over 24 years of follow-up, 3,509 deaths were confirmed, including 1,079 from CVD and 649 from cancer. Adherence to healthy dietary patterns after diagnosis (comparing the 90th with the 10th percentile of dietary pattern scores) was consistently associated with lower all-cause mortality, with multivariable-adjusted HRs ranging from 0.78 (95% CI: 0.71, 0.85) for the Planetary Health Diet to 0.92 (95% CI: 0.84, 1.01) for the Dietary Approaches to Stop Hypertension. Furthermore, greater improvements in dietary pattern adherence from pre- to post-diagnosis (comparing the 90th with the 10th percentile of change scores) were also associated with lower all-cause mortality, with HRs (95% CI) ranging from 0.63 (0.58, 0.70) to 0.92 (0.85, 1.01). A similar pattern of inverse associations with CVD mortality was also observed for these dietary scores. Additionally, the reversed Empirical Dietary Index for Hyperinsulinemia was specifically associated with lower cancer mortality. CONCLUSIONS:Adherence to healthy dietary patterns is universally associated with better survival in individuals with T2D. These findings suggest the importance of consuming high-quality diets in the prevention of premature deaths among individuals with T2D.

BACKGROUND:Alcohol consumption is common behavior among US veterans, yet its impact on long-term health outcomes remains incompletely understood. OBJECTIVE:We conducted a cohort study to examine the associations between alcohol consumption versus abstention and major adverse cardiovascular events (MACE; myocardial infarction, stroke, or cardiovascular death), cancers, and total mortality. METHODS:Self-reported alcohol consumption was collected from 438,442 participants from the prospective Million Veteran Program Study (MVP 2011-2024). The outcomes included total mortality and indent cancer and MACE. RESULTS:A J-shaped association was observed between alcohol and risk of mortality (both Ps for linear trend and curvature<0.0001) and risk of MACE (P for curvature<0.0001; P for linear trend = 0.24). Compared to never drinkers, the hazard ratio (HR) for mortality was 0.86 (0.84, 0.89) for current drinkers with alcohol 0.1-30g/d, and 0.84 (0.80, 0.89) for MACE. The HR for cancer was positively associated with higher daily intake among current drinkers: 1.03 (0.99, 1.17) [0.1-30g/d], 1.06 (1.00, 1.12) [31-60g/d], 1.20 (1.12, 1.29) [61-90g/d] and 1.28 (1.12, 1.47) [>90g/d] (P for curvature =0.06, P for linear trend<0.0001). Compared to participants who reported never smoking and never drinking, the HR for head and neck cancer was 3.21 (2.17, 4.74) among current smokers with moderate alcohol consumption (females up to 14g/d and males up to 28g/d) and 5.69 (3.76, 8.62) among current smokers with heavy drinking (P for interaction=0.03). CONCLUSIONS:Among US Veterans, alcohol consumption was associated with mortality and MACE in a J-shaped pattern, with lower risk observed at moderate consumption levels compared to abstinence or heavier drinking. However, alcohol consumption demonstrates a linear dose-response relationship with cancers, with increased risks for alcohol-related cancers even at moderate consumption levels. The alcohol and head and neck cancer association was significantly exacerbated by smoking.

INTRODUCTION:Associations of adherence to and changes in Mediterranean (MedDiet) and Mediterranean-Dietary Approaches to Stop Hypertension Intervention for Neurodegenerative Delay (MIND) diets with cognitive outcomes are unclear. METHODS:We prospectively followed 86,740 women (Nurses' Health Study, 1980-2023) and 43,500 men (Health Professionals Follow-Up Study, 1986-2023). Diet was assessed repeatedly using food frequency questionnaires. Dementia cases were identified from self-reported physician diagnoses and death records. Cognitive function was assessed by telephone tests, and subjective cognitive decline (SCD) was self-reported. RESULTS:Participants in the highest versus lowest MedDiet and MIND categories had 21% (hazard ratio [HR] = 0.79, 95% confidence interval [CI]: 0.73-0.84) and 14% (HR = 0.86, 95% CI: 0.81-0.91) lower dementia risk, respectively. Higher adherence was associated with 0.75 to 1.59 fewer years of cognitive aging, and 40% to 42% lower risk of SCD. Similar inverse associations were observed for improved adherence over 4 or 8 years. DISCUSSION:Adherence to Mediterranean and MIND diets was associated with cognitive benefits.

Importance:Evidence linking coffee and tea to cognitive health remains inconclusive, and most studies fail to differentiate caffeinated from decaffeinated coffee. Objective:To investigate associations of coffee and tea intake with dementia risk and cognitive function. Design, Setting, and Participants:Prospective cohort study that included female participants from the Nurses' Health Study (NHS; n = 86 606 with data from 1980-2023) and male participants from the Health Professionals Follow-up Study (HPFS; n = 45 215 with data from 1986-2023) who did not have cancer, Parkinson disease, or dementia at study entry (baseline) in the US. Exposures:The primary exposures were intakes of caffeinated coffee, decaffeinated coffee, and tea. Dietary intake was collected every 2 to 4 years using validated food frequency questionnaires. Main Outcomes and Measures:The primary outcome was dementia, which was identified via death records and physician diagnoses. The secondary outcomes included subjective cognitive decline assessed by a questionnaire-based score (range, 0-7; higher scores indicate greater perceived decline; cases defined as those with a score ≥3) and objective cognitive function assessed only in the NHS cohort using telephone-based neuropsychological tests such as the Telephone Interview for Cognitive Status (TICS) score (range, 0-41) and a measure of global cognition (a standardized mean z score for all 6 administered cognitive tests). Results:Among 131 821 participants (mean age at baseline, 46.2 [SD, 7.2] years in the NHS cohort and 53.8 [SD, 9.7] years in the HPFS cohort; 65.7% were female) during up to 43 years of follow-up (median, 36.8 years; IQR, 28-42 years), there were 11 033 cases of incident dementia. After adjusting for potential confounders and pooling results across cohorts, higher caffeinated coffee intake was significantly associated with lower dementia risk (141 vs 330 cases per 100 000 person-years comparing the fourth [highest] quartile of consumption with the first [lowest] quartile; hazard ratio, 0.82 [95% CI, 0.76 to 0.89]) and lower prevalence of subjective cognitive decline (7.8% vs 9.5%, respectively; prevalence ratio, 0.85 [95% CI, 0.78 to 0.93]). In the NHS cohort, higher caffeinated coffee intake was also associated with better objective cognitive performance. Compared with participants in the lowest quartile, those in the highest quartile had a higher mean TICS score (mean difference, 0.11 [95% CI, 0.01 to 0.21]) and a higher mean global cognition score (mean difference, 0.02 [95% CI, -0.01 to 0.04]); however, the association with global cognition was not statistically significant (P = .06). Higher intake of tea showed similar associations with these cognitive outcomes, whereas decaffeinated coffee intake was not associated with lower dementia risk or better cognitive performance. A dose-response analysis showed nonlinear inverse associations of caffeinated coffee and tea intake levels with dementia risk and subjective cognitive decline. The most pronounced associated differences were observed with intake of approximately 2 to 3 cups per day of caffeinated coffee or 1 to 2 cups per day of tea. Conclusions and Relevance:Greater consumption of caffeinated coffee and tea was associated with lower risk of dementia and modestly better cognitive function, with the most pronounced association at moderate intake levels.

We examined whether long-term exposure to visceral-adipose-tissue (VAT) influences brain atrophy and cognitive performance years after lifestyle intervention. In the Follow-Interventions-Trials (FIT) project, 533 adults (age=61.4 y, 86% men) from four prior 18-24-month lifestyle randomized-clinical-trials underwent abdominal/brain magnetic-resonance-imaging (MRI)s and Montreal-Cognitive-Assessment (MoCA) testing 5-16 y after interventions. Lower VAT exposure, calculated by area-under-the-curve, from baseline, post-intervention, and follow-up, independently resulted in higher MoCA scores. VAT loss during intervention predicted higher brain volumes at follow-up, independent of weight loss. Among participants with three brain and VAT MRI scans, lower long-term VAT was associated with a slower rate of brain atrophy. These patterns were not observed for deep/superficial subcutaneous-adipose-tissues. Improved glycemic control parameters, rather than lipid or inflammatory markers, were mostly related to the favorable longitudinal brain outcomes. This long-term, large-scale intervention and follow-up MRI study suggests that sustained visceral fat loss, rather than weight loss, is linked to better cognition and attenuation of brain atrophy years later, mainly via improved glycemic control. Trial registration: DIRECT (Clinical-trials-identifier: NCT00160108); CASCADE (Clinical-trials-identifier: NCT00784433); CENTRAL (Clinical-trials-identifier: NCT01530724); DIRECT-PLUS (Clinical-trials-identifier: NCT03020186).

Background The timing of exposure to diet across the lifespan may be critical in the development of T2D. However, no previous study has deciphered the influence of dietary insulinemic and inflammatory potential on the risk of T2D across the lifespan from a life course perspective. Objective This study aimed to evaluate the associations of dietary insulinemic and inflammatory potential with the risk of T2D from a life course perspective. Design This was a prospective cohort study. Participants and setting Data from 40,135 eligible, female participants in the Nurses’ Health Study II were analyzed. Adulthood diet was assessed quadrennially since 1991 using 131-item food frequency questionnaires (FFQ), and adolescent diet was recalled in 1997 using a 124-item high-school FFQ. The main exposures were empirical dietary index for hyperinsulinemia (EDIH) and empirical dietary inflammatory pattern (EDIP) scores across different life stages (adolescence, premenopausal adulthood, postmenopausal adulthood) and changes and cumulatively over the lifetime. Main outcome measures The main outcome was incident T2D. Statistical analyses performed Cox models were used to estimate hazard ratios (HR) and 95% confidence intervals (CI). Results Higher EDIH and EDIP scores (highest vs lowest quintiles) were associated with increased lifetime risk of T2D as a lifetime average (HR, 95%CI: 2.72, 2.38-3.11 and 2.04, 1.81-2.30), during premenopausal adulthood (3.18, 2.52-4.01 and 2.31, 1.88-2.82), and postmenopausal adulthood (2.67, 2.15-3.33 and 1.70, 1.41-2.05), but not during adolescence (1.07, 0.95-1.20 and 1.10, 0.98-1.24). The HR, 95%CI associated with higher lifetime averages for both EDIH and EDIP (vs. low lifetime averages for both, based on tertiles) was 2.64 (2.32-3.01). Individuals with high adulthood EDIH or EDIP had similar magnitudes of lifetime risk elevation, regardless of their adolescent EDIH and EDIP status. Adolescent EDIH and EDIP were associated with a slightly increased premenopausal T2D risk (1.24, 1.02-1.51, and 1.24, 1.02-1.50). In additional analyses estimating the time window during which adulthood dietary insulinemic and inflammatory potential influences T2D risk, higher adulthood EDIH or EDIP was associated with an increased risk of T2D with a very short time lag. Conclusions Over the life course in women, high dietary insulinemic and inflammatory potential in both premenopausal and postmenopausal adulthood were independently associated with a substantially increased lifetime risk of T2D. Adulthood offers the most critical time window for dietary interventions to reduce lifetime T2D risk, though adolescent diet may influence the risk of premenopausal T2D.

AIM:Despite growing evidence linking better oxidative balance to improved cardiometabolic health, metabolite signatures reflecting oxidative status remain still poorly characterized. We aimed to identify a plasma metabolite signature of the oxidative balance score (OBS) and to examine its association with incident cardiovascular disease (CVD) and type 2 diabetes (T2D). METHODS:The discovery population included 1732 participants at high cardiovascular risk from the PREDIMED study with available plasma metabolomics using LC-MS and OBS data at baseline. The OBS was calculated at baseline and after 1-year of follow-up based on 12 a priori selected pro- and antioxidant dietary and non-dietary lifestyle factors, with higher scores indicating a more favorable antioxidant balance. A set of metabolites predicting OBS was selected from 388 candidate metabolites using elastic net regression. Multivariable Cox models were used to examine the associations between the OBS metabolite signature and incident CVD and T2D. RESULTS:A subset of 21 metabolites was consistently selected (amino acids, vitamins, nucleotides, lipid species, xenobiotics, and others). The metabolite signature was inversely associated with incident CVD in the baseline sample (HR per SD 0.70; 95% CI 0.61-0.81), but not in the 1-year sample (HR 0.94; 95% CI 0.81-1.09). In addition, baseline (HR 0.70; 95% CI 0.60-0.80) and 1-year (HR 0.84; 95% CI 0.72-0.97) OBS metabolite signatures were inversely associated with T2D risk. CONCLUSIONS:A plasma metabolite signature reflecting oxidative balance-related exposures was inversely associated with CVD and T2D risk at baseline. The association with T2D was also observed when the signature was applied to 1-year measurements and in an independent external cohort, whereas the association with CVD was not replicated at 1 year. Most metabolites showed biologically plausible patterns, correlating with specific pro- and antioxidant exposures and including metabolites previously implicated in oxidative stress-related processes. CLINICAL TRIAL REGISTRATION:This trial was registered at controlled-trials.com as ISRCTN35739639.

BACKGROUND:Numerous carbohydrate quality metrics (CQMs) have been suggested, yet the optimal one(s) associated with the lowest type 2 diabetes (T2D) risk remains unknown. OBJECTIVES:We aimed to systematically compare 23 CQMs with T2D risk, identify the 5 strongest associations, propose an alternate Carbohydrate Quality Index (aCQI), and compare it with the existing CQI regarding T2D risk and cardiometabolic biomarkers. METHODS:We included participants of 3 prospective cohort studies [Nurses' Health Study I (1984-2020) and II (1991-2019), and Health Professionals Follow-up Study (1986-2020)], who were free of cancer, diabetes, and cardiovascular disease. Our primary outcome was incident T2D. We examined 13 plasma biomarkers in relation to CQIs among a subset. RESULTS:During 5,628,955 person-years of follow-up among 213,704 adults, 22,351 cases of incident T2D were ascertained. In multivariable-adjusted models, comparing Q5 to Q1, intakes of cereal fiber [relative risk (RR): 0.77 (0.74-0.81)], whole-fruit carbohydrates [RR: 0.80 (0.76-0.84)], glycemic index [RR: 1.20 (1.14-1.26)], sugar from sugar-sweetened beverages [RR: 1.22 (1.17-1.28)], and whole-grain carbohydrates [RR: 0.86 (0.82-0.91)] had the strongest associations with T2D risk. The aCQI [RR: 0.71 (0.68-0.75)], comprising these variables, had a larger magnitude of association with T2D risk than the original CQI [RR: 0.82 (0.79-0.87)], which included total fiber intake, glycemic index, the ratios of whole to total grains, and solid to total carbohydrates. The aCQI had significant associations with a larger percentage of differences in cardiometabolic biomarker concentrations, such as C-peptide, leptin, and LDL cholesterol, than the CQI (all P-trend ≤ 0.001). CONCLUSIONS:The novel aCQI, comprised carbohydrates from whole fruits, whole grains, sugar-sweetened beverages, cereal fiber, and glycemic index, was more strongly associated with risk of T2D and cardiometabolic biomarkers than its individual components or the existing CQI, necessitating further research.

Maternal and child overweight and/or obesity (OW/OB) are growing public health concerns, especially in low-income households, where they contribute to intergenerational transmission and increased financial burden. Using a convergent mixed methods design, this study aimed to investigate the determinants of intergenerational obesity among low-income families in Malaysia. Quantitative data were derived from the Malaysian National Health and Morbidity Survey for the years 2006, 2011, and 2015, while qualitative insights were obtained through in-depth interviews. The quantitative study included 2,057, 994, and 952 mother-child pairs from low-income households in 2006, 2011, and 2015, respectively classified based on body mass index categories. Factors associated with overweight mother/overweight child pairs (OWM/OWC) were analyzed using multiple logistic regressions. To explore the factors contributing to OW/OB, the qualitative study involved 27 in-depth interviews with mothers, and the data were analyzed using thematic analysis and findings from both studies were integrated through a narrative approach. Maternal ages between 41-50 years (2006: AOR = 2.35, 95% CI = 1.21-4.60, p = 0.012) and above 50 years (2006: AOR = 2.29, 95% CI = 1.06-4.98, p = 0.036; 2015: AOR = 3.23, 95% CI = 1.14-9.13, p = 0.025) were associated with higher odds of OWM/OWC. Children aged between 10-14 years had higher risk (2006: AOR = 2.38, 95% CI = 1.63-3.47, p < 0.001; 2011: AOR = 1.76, 95% CI = 1.05-2.96, p = 0.032). Chinese (2006: AOR = 0.46, 95% CI = 0.23-0.92, p = 0.027; 2015: AOR = 0.40, 95% CI = 0.19-0.83, p = 0.014), other ethnicities (2006: AOR = 0.49, 95% CI = 0.32-0.73, p = 0.001; 2011: AOR = 0.46, 95% CI = 0.25-0.83, p = 0.010; 2015: AOR = 0.53, 95% CI = 0.31-0.91, p = 0.020), and large household size (2015: AOR = 0.19, 95% CI = 0.04-0.94, p = 0.041) were protective against OWM/OWC. Four major themes emerged from the in-depth interviews: (1) personal factors (demographics, cognitions, and skills), (2) social environment (parent-child relationships), (3) physical environment (home and built environments), and (4) macro-level environment (food price and media influence). The findings suggest that intergenerational OW/OB in low-income households is influenced by interconnected personal factors, as well as social, physical, and macro-level environments. This study not only provides a comprehensive understanding of how such factors interact within real-life contexts but also highlights the importance of multi-level interventions that address individual behaviors and broader environmental and socio-economic constraints.