Background: While DNA methylation ( DNAm )‐based algorithms of aging show promise for predicting age‐related diseases, their comparative utility for incident cardiovascular disease ( CVD ) remains underexplored. We aimed to systematically compare 13 DNAm algorithms in relation to CVD risk in older adults. Methods: This prospective cohort study included 2112 participants from the US HRS (Health and Retirement Study) with baseline DNAm data (2016) and 6‐year follow‐up. DNAm profiling was performed using the Infinium MethylationEPIC BeadChip kit ( EPIC , Illumina, San Diego, CA ). Thirteen widely used DNAm algorithms of aging were evaluated. Cox proportional hazards models were used to estimate hazard ratios (HRs) and 95% CIs per 1‐SD increase in risk scores for incident CVD, including any CVD, congestive heart failure, and stroke. Results: During a median of 37 months’ follow‐up, a total of 288 CVD cases (congestive heart failure, 38; stroke, 152) were observed. Zhang_DNAmAge, methylation Pace of Aging, and DNAmGrimAgeAcc showed positive associations with any CVD risk, with HRs per SD increase of 1.25 (95% CI, 1.07–1.45), 1.16 (95% CI, 1.02–1.33), and 1.24 (95% CI, 1.05–1.47), respectively. For specific CVD subtypes, DNAmGrimAge was associated with congestive heart failure risk ( HR , 1.47 [95% CI, 1.11–1.95]), while both mPoA ( HR , 1.24 [95% CI, 1.03–1.49]) and HorvathAcc ( HR , 1.28 [95% CI , 1.07–1.55]) predicted incident stroke. Significant dose–response relationships ( P ‐trend <0.05) were observed for Zhang_DNAmAge and DNAmGrimAgeAcc across all CVD outcomes. Conclusions: Zhang_DNAmAge, methylation Pace of Aging, and DNAmGrimAgeAcc function as independent predictors of incident CVD . These epigenetic biomarkers may improve early CVD detection and risk stratification in aging populations.

Although obesity is a well-established risk factor for metabolic dysfunction-associated steatotic liver disease (MASLD), the impact of long-term weight trajectories on MASLD risk remains unclear. We aimed to examine the association between weight change trajectories across adulthood and the risk of ultrasound-defined MASLD. We analysed data from 4999 participants from the Healthy Happy Aging Community Cohort. Weight trajectories were assessed using body mass index (BMI) at age 25 years, ten years before baseline, one year before baseline, and at baseline. MASLD was defined as a median (MD) controlled attenuation parameter (CAP) of ≥274 dB/m and severe steatosis as a MD CAP of ≥302 dB/m via vibration-controlled transient elastography. There were 2247 (44.9%) patients with MASLD, of whom 1468 (29.4%) had severe steatosis. Compared with stable normal weight, sustained obesity (BMI ≥ 30 kg/m² at all time points) demonstrated a strong association with MASLD risk (adjusted odds ratio (aOR) = 2.17; 95% confidence interval (CI) = 1.64-2.86), particularly for severe steatosis (aOR = 2.52; 95% CI = 1.74-3.66). The transition from non-obese to obese status was associated with a 2.5-fold increase in risk (aOR = 2.51; 95% CI = 1.81-3.48), with a more pronounced effect observed in men (P-interaction <0.05). Weight gain of ≥5 kg between ages 25-40 years showed particularly strong associations (aOR = 2.20; 95% CI = 1.70-2.86), while baseline severe obesity (BMI ≥ 35 kg/m²) remained the strongest independent predictor (aOR = 4.12; 95% CI = 2.70-6.29). Long-term obesity and weight gain, especially in early adulthood, significantly increase MASLD risk. Sustained obesity and progression to obesity were key risk factors, with severe obesity showing the strongest association. Early weight management is crucial for MASLD prevention.

Background: Rural communities in Southwest China are undergoing rapid nutrition and lifestyle transitions, with sustained positive energy balance and long-term weight gain. These settings are often ethnic minority-dominant and characterized by higher habitual alcohol consumption than most other Chinese populations. Evidence on how life-course adiposity relates to metabolic liver fat burden in such a rural community with varying alcohol drinking frequency remains limited. We examined associations of current BMI, life-course BMI trajectories, and long-term BMI change with controlled attenuation parameter (CAP)-defined hepatic steatosis. Methods: We conducted a retrospective cohort analysis embedded within a routine health examination program in Ning’er County, Yunnan Province, China. Adults who underwent an index examination including vibration-controlled transient elastography (VCTE) were included. Hepatic steatosis and severe steatosis were defined as CAP ≥238 and ≥292 dB/m, respectively. Body weight and height at ages 18, 30 and 40 years were extracted from prior health examination records, and BMI at each time point was calculated and categorized using Chinese cut-offs to construct life-course trajectory patterns. Multivariable logistic regression estimated odds ratios (ORs) for CAP-defined outcomes adjusting for age, sex, ethnicity, smoking, and past-year alcohol drinking frequency, with further adjustment for waist circumference and metabolic and liver biomarkers. Restricted cubic splines evaluated dose–response associations between long-term BMI change (ΔBMI from age 18 to the index examination) and steatosis. Results: Among 956 adults (predominantly ethnic minorities), the prevalence of CAP-defined steatosis and severe steatosis was 52.9 and 18.2%, respectively. Higher current BMI and weight-gain or persistent-obesity trajectory patterns were associated with greater odds of steatosis and severe steatosis. After additional adjustment, BMI ≥ 28.0 kg/m ² remained independently associated with steatosis (OR 2.08; 95% CI 1.05–4.14), whereas associations with severe steatosis were attenuated. Long-term BMI gain was monotonically associated with steatosis, with the OR becoming statistically significant at ΔBMI 6.64 kg/m ² . Alcohol drinking frequency showed no strong independent association with CAP-defined outcomes. Conclusion: In this ethnic minority-dominant rural population with relatively frequent self-reported alcohol use, sustained weight gain across adulthood and adverse life-course BMI trajectories were associated with a higher burden of CAP-defined hepatic steatosis and severe steatosis. These findings support the importance of life-course weight maintenance for reducing liver fat accumulation in rural community settings.