Background: Plant-based diets are increasingly advocated for their health benefits, yet their associations with dementia risk remains inconclusive. We evaluated the associations between plant-based dietary patterns and dementia risk across three prospective cohorts and a meta-analysis. Methods: Cohort analyses included the Health and Retirement Study (HRS; N = 6642), Framingham Heart Study Offspring cohort (FOS; N = 3045), and Whitehall II study (WHII; N = 8219). Participants were aged ≥45 years and free of dementia at baseline. The overall plant-based diet index (PDI), healthful plant-based diet index (hPDI) and unhealthful plant-based diet index (uPDI) were calculated from validated food frequency questionnaires. Further, a meta-analysis was conducted incorporating data from 5 cohort studies (N = 207,981). Results: In the cohort analyses, 891 incident dementia cases were identified over 166,762 person-years. In multivariable-adjusted Cox proportional hazard models, higher scores in PDI and hPDI were associated with lower risk of dementia (highest vs. lowest tertile: pooled HR for PDI = 0.70, 95% CI, 0.53–0.92, p for trend <0.001; pooled HR for hPDI = 0.71, 0.48–1.06, p for trend = 0.03). Main contributors to lower risk were higher intake of vegetables, nuts, tea or coffee, and legumes. Conversely, higher uPDI was associated with higher dementia risk (highest vs. lowest tertile: pooled HR = 1.42, 1.19–1.70, p for trend <0.001). In the meta-analysis, individuals in the highest hPDI tertile had 21% lower dementia risk, and those in the highest uPDI tertile had 24% higher risk. Conclusions: The healthful plant-based diet was associated with lower risk of dementia, whereas the unhealthful plant-based diet was linked to higher risk. These findings support recommendations to adopt diets rich in healthy plant foods for dementia prevention.

BACKGROUND & AIMS:Endothelial cell (EC) damage is an initiating event in acute cellular rejection after liver transplantation (LT). However, the origin and characteristics of post-transplant neonatal ECs remain controversial. We aimed to uncover the mechanisms underlying EC-T cell interactions after transplantation and to develop an EC-targeted strategy to alleviate transplant rejection. METHODS:Leveraging single-cell RNA sequencing from 13 human and 4 murine liver allografts, we mapped the functional atlas of ECs. Allogeneic orthotopic LT in CAG;R26-tdTomato and Cd34-CreERT2;R26-tdTomato mice confirmed the cellular origin of ECs. We used CellChat, multiplex immunohistochemistry, and in vitro co-culture models to investigate the mechanism of EC-T cell interactions. Using a platelet-based bio-delivery system, we achieved targeted delivery of a CXCL12 monoclonal antibody (αCXCL12). RESULTS:ECs in transplanted livers exhibited a dual origin, being derived from both donor and recipient cells. Recipient-derived ECs were characterized by high CD34 expression, high stemness, and pro-inflammatory characteristics. Using genetic lineage-tracing mice combined with an orthotopic LT model, we found that recipient CD34+ cell-derived ECs peaked at 2 weeks post-LT and declined by 4 weeks, consistent with the temporal pattern of rejection. We further identified that CD34+ ECs recruit and potentiate Th1 and cytotoxic CD8+ T cells via the CXCL12-CXCR4 axis and co-stimulatory molecules. In turn, cytotoxic CD8+ T cells induced pyroptosis of CD34+ cell-derived ECs through the Caspase1-GSDMD pathway. Platelets loaded with αCXCL12 specifically targeted ECs in the transplanted liver, reducing T-cell infiltration and mitigating rejection. CONCLUSIONS:We identified a population of recipient-derived CD34+ ECs that exacerbates acute rejection by activating T cells through the CXCL12-CXCR4 axis. We further developed a platelet-based delivery strategy that precisely targets EC-derived CXCL12 and effectively prevents acute cellular rejection. IMPACT AND IMPLICATIONS:We integrated single-cell transcriptomic data from human and murine liver allografts to delineate the dual cellular origins and functional atlas of endothelial cells. Using lineage-tracing mice in an allogeneic orthotopic liver transplantation model, we tracked the fate of CD34+ cells and demonstrated the contribution of recipient-derived CD34-lineage endothelial cells to liver allograft angiogenesis. These CD34-lineage endothelial cells recruited T cells through the CXCL12-CXCR4 axis and activated them via co-stimulatory molecules. Furthermore, a platelet-based biological delivery strategy targeting CXCL12 in CD34-lineage endothelial cells alleviated T cell-mediated rejection. This study provides an endothelial cell-centered perspective and proposes a potential novel immunosuppressive strategy for liver transplantation.

The gut microbiome may shape how diet influences cognitive aging, but population-based evidence remains limited. In 784 older adults living in rural China (70-98 years old) with fecal metagenomics and structured dietary assessment, a modified healthful plant-based diet index (mHPDI) is associated with distinct gut microbial structure and taxonomic shifts (15 species, 17 genera). Among participants with repeated cognitive measurements, higher mHPDI is associated with better global cognition, with stronger benefits in participants with non-Prevotella-dominant enterotypes (highest versus lowest tertile β = 0.34, 95% confidence interval [CI], 0.16 to 0.52) than in those with a Prevotella-dominant enterotype (0.04, -0.22 to 0.29; p interaction = 0.04). Enterotype-associated differences in microbial metabolic pathways, including preQ0 and L-isoleucine biosynthesis, parallel this heterogeneity. Moreover, 12 circulating microbiota-related metabolites (primarily amino acids and short-chain fatty acids) are linked to mHPDI. A composite score comprising these metabolites mediates 11.0% of the mHPDI-cognition association (p mediation = 0.02), with branched-chain amino acids as major contributors. These findings suggest that gut microbial context may shape diet-cognition associations.

BACKGROUND:Evidence linking intake of total and specific types of vegetable and fruit to dementia remains scarce. OBJECTIVES:This study aimed to examine associations between intake of total and specific subgroups of vegetables and fruits and dementia risk across 3 prospective cohorts and a meta-analysis. METHODS:Data were drawn from the Health and Retirement Study (HRS), the Framingham Heart Study Offspring Cohort (FOS), and the Whitehall II Study (WHII). Mean daily intakes of total vegetables and fruits, and 7 subgroups, were assessed using food frequency questionnaires. Incident dementia was identified using cohort-specific definitions. Cox regression models were used to estimat hazard ratios (HRs) and 95% confidence intervals (CIs). We also performed a meta-analysis that incorporated our results and findings from 13 previous cohort studies. RESULTS:Among 18,339 participants aged ≥45 y (HRS: 6750; FOS: 3068; WHII: 8521), 936 dementia cases occurred over an average 7-13 y follow-up period. After multivariable adjustment, intake of total fruits and vegetables was associated with a lower risk of dementia in the highest compared with the lowest tertile (HR T3 compared with T1 was 0.74, 95% CI: 0.61, 0.89, P-trend = 0.165). Additionally, green leafy vegetables demonstrated a protective association (pooled HR per serving increment: 0.82; 95% CI: 0.70, 0.96, P-trend = 0.015). No significant pooled associations were observed for other vegetable or fruit subgroups. Findings pooled from a meta-analysis of 222,108 participants showed that a higher intake of fruits and vegetables was associated with a lower risk of dementia compared with a lower intake (pooled HR highest compared with lowest: 0.80; 95% CI: 0.71, 0.91). Significant inverse associations were also observed for vegetable intake (pooled HR highest compared with lowest: 0.87; 95% CI: 0.82, 0.92) and fruit intake (pooled HR highest compared with lowest: 0.90; 95% CI: 0.85, 0.95). CONCLUSIONS:Our study supports an inverse association of intake of vegetables and fruits with dementia risk. Further studies on specific subgroups are warranted. This meta-analysis was registered at PROSPERO as CRD42024525765.

BACKGROUND:The MIND diet was favourably linked to lower risk of neurodegenerative diseases. While previous cross-sectional studies implied its beneficial associations with brain imaging markers, its associations with long-term brain structural changes remained unclear. METHODS:We included 1647 middle-aged and older individuals from the Framingham Heart Study Offspring cohort (FOS). MIND diet score was calculated from a validated FFQ, repeatedly administered at Exams 5, 6, and 7. Brain imaging markers were acquired between 1999 and 2019, with a median repetition (interquartile range, IQR) of 3 (2-3) times. We used linear mixed models to assess the associations of the MIND diet score and its components with longitudinal brain structural changes. RESULTS:Over a median follow-up of 12.3 years (IQR 6.8-13.8 years), greater adherence to the MIND diet was associated with slower decline in total grey matter volume. Specifically, each three-unit increase in the MIND diet score was linked to a 0.279 cm³/year (95% CI 0.089 to 0.469) slower decline in total grey matter volume, corresponding to a 20.1% attenuation in age-related change that was equivalent to 2.5 years of reduced brain ageing during the 12.3-year follow-up. Additionally, higher MIND diet score was associated with slower increases in lateral ventricular volume (-0.071 cm³/year, 95% CI -0.125 to -0.017), notably in the left lateral ventricle (-0.041 cm³/year, 95% CI -0.070 to -0.013), reflecting approximately 8.0% and 8.8% attenuation of age-related changes, equivalent to roughly 1.0 year of delayed brain ageing during follow-up. CONCLUSIONS:In this prospective cohort study, greater adherence to the MIND diet was associated with slower brain structural atrophy, particularly regarding grey matter loss and ventricular enlargement. These findings support the potential of the MIND diet as a strategy to support brain health and delay structural brain ageing.

Dementia is a growing global health challenge with limited pharmacological treatments. Emerging evidence from randomized controlled trials and prospective cohort studies suggests that healthy dietary patterns may contribute to the prevention or delay of cognitive decline. This review summarizes current evidence on the relations of overall dietary patterns and specific foods and nutrients to cognitive aging, with a particular focus on the potential role of gut microbiota, which is largely shaped by diet. Certain healthy dietary patterns, such as the Mediterranean and the Mediterranean–DASH Intervention for Neurodegenerative Delay (MIND) diets, characterized by specific foods (e.g., vegetables and fruits) and dietary nutrients (e.g., n-3 fatty acids, B vitamins, and carotenoids) have shown potential benefits on cognitive health. However, inconsistencies across study findings necessitate further investigation. We review how the gut microbiota may mediate or moderate the diet-cognition association, or serve as a marker for cognitive health, particularly through mechanisms involving metabolic, immune, and neuroinflammatory pathways. Finally, we highlight key methodological challenges, including variability in exposure assessment, study design, and population heterogeneity, and propose a roadmap for future research, advocating for large-scale, multi-omics studies across diverse populations. These efforts are expected to facilitate the development of precision nutrition strategies for the prevention of cognitive decline and dementia.

Pancreatic cancer prognosis is shaped by host factors and the tumor microenvironment. Here, we identify a survival advantage in young female (≤55 years) pancreatic cancer patients-absent in older patients and males. Integrated analysis of SEER and TCGA datasets reveals that host immune and inflammatory pathways associated with bacterial response are enriched in young males, old males, and old females, but notably absent in young females. Direct microbial profiling of 30 pancreatic tumors shows that young female tumors harbor a distinct microbiome with lower Staphylococcus abundance. Functional experiments in a murine model further demonstrate that Staphylococcus promotes tumor growth in an estrogen-dependent manner, providing experimental evidence consistent with the clinical association. Older female tumors exhibit distinct microbial metabolic pathways. Our findings suggest that age and sex jointly shape the pancreatic tumor microbiome, highlighting demographic-specific approaches in cancer microbiology.

PURPOSE:Previous studies have reported inconsistent associations of coffee and tea consumption with cardiovascular disease (CVD). The mixed findings may partly reflect differences in the habitual addition of sweeteners to coffee and tea, a factor not considered in most previous studies. We aimed to evaluate the dose-response associations of unsweetened and sweetened coffee and tea consumption with incident CVD. METHODS:This prospective cohort study included 167,142 UK Biobank participants without prevalent CVD at baseline. Beverage intake and sweetener use were assessed using repeated web-based 24-h dietary recalls. Incident CVD was defined as the first recorded occurrence of coronary heart disease, stroke, or heart failure. Hazard ratios (HRs) and 95% confidence intervals (CIs) were estimated using Cox regression models. RESULTS:During a median follow-up of 11.1 years, 14,395 participants developed incident CVD. Unsweetened coffee showed a U-shaped association with incident CVD (P-nonlinearity < 0.001), with the lowest risk observed at 2.5 units/day. Compared with non-consumers, participants who consumed > 0-5 units/day of unsweetened coffee had a lower CVD risk, with HRs (95% CIs) of 0.89 (0.84-0.94) for > 0-1 unit/day, 0.90 (0.85-0.95) for > 1-2 units/day, 0.81 (0.76-0.86) for > 2-3 units/day, and 0.86 (0.81-0.91) for > 3-5 units/day, respectively. However, no significant association was observed for > 5 units/day unsweetened coffee (HR: 1.00, 95% CI: 0.91-1.11). Sweetened coffee consumption was not associated with a lower CVD risk at any intake level. Similarly, unsweetened tea was associated with a lower CVD risk across intake categories, whereas high sweetened tea intake was associated with higher a CVD risk (HR: 1.13, 95% CI: 1.01-1.26 for > 5 units/day). CONCLUSIONS:Moderate intakes of unsweetened coffee and tea were each associated with a lower risk of incident CVD, whereas sweetened types did not show protective associations. These findings suggest that sweetener use should be considered when evaluating the cardiovascular relevance of coffee and tea consumption.

Background/Objectives: Nuts have been associated with various health benefits, yet the evidence regarding their relationship with dementia is inconclusive. This study aims to examine the association between nut consumption and long-term risk of dementia across three prospective cohort studies. Methods: We analyzed data from adults aged 45 and older who were free of dementia at baseline in the Health and Retirement Study (HRS, 2013-2020), the Framingham Offspring Study (FOS, 1998-2018), and the Whitehall II Study (WHII, 2002-2016). Nut consumption, including tree nuts and peanuts, was assessed using validated food frequency questionnaires (FFQs) once at baseline in the HRS and repeatedly across multiple waves in the FOS and WHII. Incident all-cause dementia was identified through a validated algorithm in the HRS, expert panel reviews in the FOS, and healthcare record linkages in the WHII. Cox proportional hazards models were used to estimate the cohort-specific association between nut consumption and incident dementia, which were subsequently pooled. Results: Over 190,914 person-years of follow-up, 992 incident dementia cases occurred among 17,349 participants across the three cohorts. After multivariable adjustments, higher nut consumption was associated with a lower risk of dementia, with pooled hazard ratios (HRs) of 0.80 (95% confidence interval [CI]: 0.69-0.94; I-2 = 0.0%) for 0.1-5.0 g/day vs. 0 g/day and 0.76 (95% CI: 0.58-0.99; I-2 = 40.4%) for >5.0 g/day vs. 0 g/day (p-trend = 0.015). Conclusions: Our findings suggest that higher nut consumption was associated with a lower risk of incident dementia among middle-aged and older adults, with evidence of a dose-response trend observed in pooled analyses. These preliminary results support its inclusion as part of an overall brain-healthy dietary pattern.

Importance:Healthier diets are generally believed to benefit cognitive health; however, the evidence remains inconsistent, and a systematic examination of multiple healthy dietary patterns within the same context is lacking. Objective:To evaluate the associations of 6 healthy patterns with subjective cognitive decline (SCD) and objective cognitive function. Design, Setting, and Participants:This was a prospective cohort study based on the Nurses' Health Study (NHS, 1986-2014), NHSII (1991-2017), and the Health Professionals Follow-Up Study (HPFS, 1986-2012). Included were adults with available data on diet and cognitive function. Data analyses were performed from September 2024 to November 2025. Exposures:Six dietary pattern scores, including the Alternate Healthy Eating Index 2010 (AHEI-2010), the Dietary Approaches to Stop Hypertension (DASH) diet score, the Healthful Plant-Based Diet Index (hPDI), the Planetary Health Diet Index (PHDI), and the reversed empirical dietary indices for hyperinsulinemia (rEDIH) and inflammatory pattern (rEDIP). Main Outcomes and Measures:SCD was assessed using 7 questions on perceived cognitive changes. Cognitive function was objectively measured via telephone in the NHS. Results:A total of 159 347 individuals (mean [SD] age, 44.3 [9.3] years; 131 560 female [82.6%]) were included in this analysis. Among the study participants, higher adherence to all 6 dietary patterns was associated with a lower SCD risk. The DASH diet showed the strongest magnitude (risk ratio [RR] comparing 90th vs 10th percentile of adherence: 0.59; 95% CI, 0.57-0.62), followed by the hPDI (RR, 0.76; 95% CI, 0.65-0.85), rEDIH (RR, 0.76; 95% CI, 0.73-0.80), PHDI (RR, 0.80; 95% CI, 0.75-0.86), AHEI-2010 (RR, 0.84; 95% CI, 0.80-0.89), and rEDIP (RR, 0.89; 95% CI, 0.85-0.93). Higher DASH diet score at ages 45 to 54 years showed the strongest association with SCD. Higher adherence to the DASH diet also showed the strongest association with a higher objectively measured global cognition (mean z score difference comparing 90th vs 10th percentile: 0.05; 95% CI, 0.02-0.09). Key food groups associated with better cognitive function included higher vegetable and fish intake and lower red and processed meats intake. Conclusions and Relevance:Results reveal that healthy diets, exemplified by the DASH diet for blood pressure control and diets with lower hyperinsulinemia and inflammation potentials, were associated with a lower SCD risk and better cognitive function. These findings underscore the importance of a healthy diet for maintaining long-term cognitive health.

Mild cognitive impairment (MCI) is a high-risk state for Alzheimer's disease (AD), and reliable prediction of MCI-to-AD conversion is crucial for early intervention. This study proposes a quaternion-based functional connectivity (QFC) framework for multi-band analysis of resting-state fMRI (rs-fMRI) signals to predict conversion from MCI to AD over a 5-year period. In contrast to conventional independent band or simple concatenation approaches, the proposed QFC representation preserves the multidimensional structure of the signal and enables a holistic characterization of cross-frequency relationships. QFC features were extracted from multi-band rsfMRI data and used as input to machine learning classifier. The proposed method achieved superior performance compared with single-band features and a traditional multi-band concatenation strategy, yielding an accuracy of 87.8%, a sensitivity of 90.7%, a specificity of 84.4%, a mean F1-score of 0.877, and an area under the ROC curve of 0.937 using the Naïve Bayes classifier. These results correspond to relative improvements of 16%, 20%, 11%, 16%, and 14% in accuracy, sensitivity, specificity, F1-score, and AUC, respectively, over the traditional multi-band approach. The findings highlight the effectiveness of QFC for capturing frequency-dependent alterations in functional connectivity and underscore its potential for early and accurate prediction of MCI-to-AD conversion from a clinical perspective.

BACKGROUND:Low-carbohydrate and low-fat diets (LCDs and LFDs) are promoted for cardiometabolic prevention, but their associations with cognitive outcomes remain unclear. OBJECTIVES:To examine the associations of LCDs and LFDs with incident dementia and evaluate the modification by genetic susceptibility. METHODS:We included 5301 dementia-free adults aged ≥55 y from the Health and Retirement Study. Overall LCD and LFD scores were constructed based on macronutrient composition rankings assessed using a food frequency questionnaire in 2013‒2014. Plant-based, animal-based, healthy, and unhealthy subtype scores were derived to characterize macronutrient sources and quality. Incident dementia was defined using the Langa-Weir algorithm through 2022. Genetic susceptibility was assessed using apolipoprotein E (APOE) genotype and Alzheimer's disease polygenic risk score (AD-PRS). Cox models estimated hazard ratios (HRs). RESULTS:During the 9-y follow-up, 506 participants developed dementia. A higher LCD score was associated with lower dementia risk [hazard ratio (HR) per standard deviation (SD) increment: 0.90; 95% confidence interval (CI): 0.82, 0.99], whereas an overall LFD was not (HR per SD: 1.05; 95% CI: 0.96, 1.15). Plant-based and healthy LCDs showed stronger inverse associations (HR per SD: 0.85; 95% CI: 0.78, 0.94 and HR per SD: 0.82; 95% CI: 0.74, 0.90), whereas higher animal-based LFDs (HR per SD: 1.10; 95% CI: 1.00, 1.20) and unhealthy LFDs (HR per SD: 1.13; 95% CI: 1.04, 1.24) were linked to higher dementia risk. Associations were consistent across APOE genotype and AD-PRS strata. Higher plant-based and healthy LCDs were also associated with better global and domain-specific cognitive performance. CONCLUSIONS:Higher adherence to LCDs, particularly plant-based and healthy LCDs, is associated with lower dementia risk, consistently across genetic susceptibility strata. These findings underscore the importance of macronutrient quality, in addition to quantity, in promoting cognitive health.

Choline plays key roles in neurotransmitter synthesis and membrane integrity, processes fundamental to brain function. However, evidence from population studies on the association of dietary choline intake with dementia risk is mixed. We analyzed data of 5,301 dementia-free participants (mean age = 68.6 years; 59

BACKGROUND AND OBJECTIVES:Smoking cessation is universally prioritized for the prevention of cardiovascular disease and cancer, but its impact on dementia risk remains uncertain. We aimed to evaluate the associations of smoking cessation and postcessation weight gain with long-term risk of dementia and cognitive trajectories. METHODS:We conducted a prospective cohort study using data from the US Health and Retirement Study (1995-2020). A total of 32,802 dementia-free adults (mean age 60.5 years [SD 10.7]; 57.1% female) were included. Smoking status and body weight were assessed biennially through structured interviews. The primary outcome was incident dementia identified using the Langa-Weir algorithm, and the secondary outcome was cognitive function measured on a 27-point scale. RESULTS:Over 25 years of follow-up (median 9.9 years, interquartile range 4.4-16.4 years), 5,868 dementia cases were documented. Compared with current smokers, individuals who quit during follow-up had a lower dementia risk after quitting (hazard ratio 0.84, 95% CI 0.73-0.95), similar to those who had quit before baseline (0.79, 0.72-0.87) and to never smokers (0.75, 0.69-0.83). The benefits of cessation were largely limited to participants with no or modest 2-year postcessation weight gain (≤5 kg). By contrast, the association of quitting accompanied by >10-kg weight gain was not statistically significant (1.33, 0.87-1.82). Restricted cubic spline analysis showed decreasing dementia risk with longer time since quitting, and the risk approached that of never smokers and plateaued at around 7 years after cessation. Cognitive trajectory analyses showed that quitting was associated with long-term slower cognitive decline (slope difference 0.19 points per decade, 95% CI 0.00-0.38) but no transient cognitive change (0.57; 95% CI -0.69 to 1.83), especially among those with minor weight gain (slope difference 0.23 per decade, 95% CI 0.03-0.43). DISCUSSION:Smoking cessation was associated with a sustained lower dementia risk and slower cognitive decline, comparable to never smokers and those without short-term risk increase. However, postcessation weight gain may attenuate these advantages, highlighting the need for weight management in cessation programs. These findings should be interpreted cautiously, given the potential residual confounding and measurement error.

BACKGROUND:The risk of recurrence remains high among patients with coronary heart disease (CHD). Life's Simple 7 (LS7), a composite indicator of cardiovascular health, has been associated with a lower risk of incident CHD, but its prognostic value among patients with CHD remains unclear. We aimed to examine the association between temporal changes in LS7 and recurrent CHD. METHODS:Data were from the US ARIC study (Atherosclerosis Risk in Communities). LS7 scores were assessed at Visit 1 (1987-1989) and Visit 3 (1993-1995). LS7 changes were evaluated by change in LS7 category (from poor/fair [0-6] to moderate/ideal [7-14] or from moderate/ideal to poor/fair), cumulative LS7 score (as quartiles), and change in LS7 score (as quartiles). Recurrent CHD was identified through December 31, 2018. Cox models assessed the association between changes in LS7 and recurrent CHD risk. RESULTS:Among 1330 participants (mean [SD] age, 55.2 [5.6] years, 50.2% female) included in transition analyses, 561 (42.2%) experienced recurrent events during 21 359.2 person-years of follow-up. Participants whose LS7 score improved from poor/fair to moderate/ideal showed a reduced risk of recurrent CHD (hazard ratio, 0.54 [95% CI, 0.40-0.74]), whereas those whose score declined from moderate/ideal to poor/fair exhibited an increased risk (hazard ratio, 1.82 [95% CI, 1.44-2.30]). Both a higher cumulative LS7 score and a greater increase in LS7 score were associated with a lower risk of recurrent CHD (hazard ratio, 0.38 [95% CI, 0.30-0.49] for Q4 versus Q1 of cumulative score and hazard ratio, 0.51 [95% CI, 0.38-0.68] for Q4 versus Q1 of Δscore). CONCLUSIONS:Deterioration in LS7 during follow-up was associated with an increased risk of recurrent CHD, whereas improvement in LS7 was associated with a reduced risk. These findings underscore the importance of preserving and improving cardiovascular health and support the potential value of longitudinal cardiovascular health assessment in the ongoing management of patients with CHD.

Diet is an essential factor influencing biological aging, yet few exsiting dietary indices were specifically developed to target biological aging. We developed a data-driven food-based Empirical Dietary Index for Slower Epigenetic Aging (EDISEA) in the US Health and Retirement Study (HRS, n=7,398), which predicted deceleration of GrimAge, an established DNA methylation-based epigenetic clock. Participants in the highest versus lowest EDISEA quintile had 4.65-year deceleration in GrimAge (P value <0.001). We externally validated EDISEA in an independent US cohort (n=23,830), where it showed consistent associations with several epigenetic clocks and lower all-cause mortality risk. In HRS and a UK aging cohort (n=4,895), EDISEA was associated with lower risks of several aging-related diseases and functional limitations. Outcome-wide analyses in the UK Biobank (n=187,035), together with integrative proteomic, metabolic, and neuroimaging assessments, revealed biological signatures of EDISEA implicating broad vascular, inflammatory, metabolic, and brain-structural pathways through which EDISEA was associated with biological aging. EDISEA provides a scalable, biologically anchored tool to inform the development of precision nutrition strategies aimed at slowing epigenetic aging and mitigating aging-related disease burden. ### Competing Interest Statement The authors have declared no competing interest. ### Funding Statement This study was supported by the Fundamental Research Funds for the Central Universities (2025ZFJH01, to BL). ### Author Declarations I confirm all relevant ethical guidelines have been followed, and any necessary IRB and/or ethics committee approvals have been obtained. Yes The details of the IRB/oversight body that provided approval or exemption for the research described are given below: The study used ONLY openly available human data that were originally located at: The Health and Retirement Study (HRS) data are available through the University of Michigan and the National Archive of Computerized Data on Aging (NACDA) subject to their data use policies. NHANES data are publicly available from the U.S. Centers for Disease Control and Prevention. English Longitudinal Study of Ageing (ELSA) data are available via the UK Data Service under standard access procedures. The UK Biobank data are available through application to the UK Biobank (application ID: 816009). I confirm that all necessary patient/participant consent has been obtained and the appropriate institutional forms have been archived, and that any patient/participant/sample identifiers included were not known to anyone (e.g., hospital staff, patients or participants themselves) outside the research group so cannot be used to identify individuals. Yes I understand that all clinical trials and any other prospective interventional studies must be registered with an ICMJE-approved registry, such as ClinicalTrials.gov. I confirm that any such study reported in the manuscript has been registered and the trial registration ID is provided (note: if posting a prospective study registered retrospectively, please provide a statement in the trial ID field explaining why the study was not registered in advance). Yes I have followed all appropriate research reporting guidelines, such as any relevant EQUATOR Network research reporting checklist(s) and other pertinent material, if applicable. Yes All data used in this study are available from the respective cohorts under data access agreements and restrictions. The Health and Retirement Study (HRS) data are available through the University of Michigan and the National Archive of Computerized Data on Aging (NACDA) subject to their data use policies. NHANES data are publicly available from the U.S. Centers for Disease Control and Prevention. English Longitudinal Study of Ageing (ELSA) data are available via the UK Data Service under standard access procedures. The UK Biobank data are available through application to the UK Biobank (application ID: 816009).

BACKGROUND:The population distribution of age-related functional impairments (ARFIs) and their associations with mortality and life expectancy (LE) among Chinese adults remain poorly understood. METHODS:We included 12,906 participants (mean age: 62.6 years) from the China Health and Retirement Longitudinal Study. Visual impairment, hearing impairment, cognitive impairment, sleep disorder, depressive symptoms, and disability in activities of daily living (ADL) were assessed. Cox proportional hazards models were used to estimate the associations of ARFIs with all-cause mortality. Life expectancy at age 50 was estimated by the presence and number of key ARFIs. RESULTS:The six ARFIs exhibit distinct distributions by ages and provinces across China. During the 9-year follow-up, ADL disability, cognitive impairment, and depressive symptoms are independently associated with 64% (95% confidence interval [CI]: 48%-80%), 41% (21%-64%), and 20% (8%-33%) higher risks of mortality, corresponding to LE losses of 4.45, 3.08, and 1.59 years at the age of 50 years. A greater number of key ARFIs is associated with higher mortality risk in a dose-response manner (hazard ratios [95% CI] vs. none: 1.23 [1.11-1.36] for one, 1.42 [1.26-1.61] for two, and 1.86 [1.47-2.36] for three) and greater LE loss (1.63 [1.35-1.90] years for one, 3.37 [3.02-3.71] for two, and 4.96 [4.22-5.71] for three, with three ARFIs accounting for 17% of total LE). CONCLUSIONS:The study highlights the important roles of co-existing ARFIs in mortality and LE loss. Integrated prevention strategies and management systems for multiple functional impairments are warranted in the context of rapid population aging.