Background and Aims: NAFLD strongly associates with cardiovascular disease (CVD) risk factors; however, the association between NAFLD and incident CVD, CVD-related mortality, incident cancer, and all-cause mortality is unclear. Approach and Results: We included 10,040 participants from the Framingham Heart Study, the Coronary Artery Risk Development in Young Adults Study, and the Multi-ethnic Study of Atherosclerosis to assess the longitudinal association between liver fat (defined on CT) and incident CVD, CVD-related mortality, incident cancer, and all-cause mortality. We performed multivariable-adjusted Cox regression models including age, sex, diabetes, systolic blood pressure, alcohol use, smoking, HDL, triglycerides, and body mass index at baseline or time-varying covariates. The average age was 51.3±3.3 years and 50.6% were women. Hepatic steatosis was associated with all-cause mortality after 12.7 years of mean follow-up when adjusting for baseline CVD risk factors, including body mass index (HR: 1.21, 1.04–1.40); however, the results were attenuated when utilizing time-varying covariates. The association between hepatic steatosis and incident CVD was not statistically significant after we accounted for body mass index in models considering baseline covariates or time-varying covariates. We observed no association between hepatic steatosis and CVD-related mortality or incident cancer. Conclusions: In this large, multicohort study of participants with CT-defined hepatic steatosis, accounting for change in CVD risk factors over time attenuated associations between liver fat and overall mortality or incident CVD. Our work highlights the need to consider concurrent cardiometabolic disease when determining associations between NAFLD and CVD and mortality outcomes.

Background:The effect of an intensive lifestyle intervention (ILI) on Alzheimer's disease (AD) blood-based biomarker levels and cognitive outcomes among individuals with type 2 diabetes (T2D) is unknown. We examined AD biomarkers and cognitive outcomes in the Look AHEAD Study. Method: Participants aged 45-76 years were randomized at baseline to a 10-year ILI or a diabetes support and education (DSE) condition. Cognitive assessments at years 8-18 included measures of attention, executive function, global function, and memory. Mild cognitive impairment (MCI) and probable dementia were adjudicated by an expert panel. Stored baseline and end-of-intervention plasma samples were analyzed with the Quanterix Simoa HD-X Analyzer. Changes in Aβ 42 /Aβ 40, ptau181, neurofilament light chain (NfL), and glial fibrillary acidic protein (GFAP) were evaluated in relation to randomization status, demographic characteristics, and cognitive outcomes. Cognitive scores and biomarker levels were converted to z-scores. Cognitive trajectories were evaluated using mixed models to account for repeated measures; logistic regression was used for a composite outcome of MCI/dementia. Models were adjusted for baseline characteristics (age, sex, education, race/ethnicity, body mass index (BMI), CVD history, hypertension, diabetes duration, eGFR), APOE-ε4, randomization arm, time from randomization, and time between blood draw and cognitive testing. Result:The mean age of 779 participants was 61.4 years; 56% = female, 22.8% = APOE ε4+, mean BMI = 34.8, baseline diabetes duration >5 years = 57%, 16.7% Black, 12.5% Hispanic, 66.2% White, and 4.7% other racial and ethnic groups. There were no associations between the intervention and biomarker levels at baseline or biomarker change over time. Increases in NfL levels significantly predicted lower memory (-0.04 ±0.01; p = 0.002), global cognition scores (-0.05 ±0.02; p = 0.011), executive function (-0.04 ±0.01; p = 0.01), as well as increased risk of MCI/probable dementia (odds ratio [OR]

In a cross-sectional analysis, we identified aging-associated monocyte transcriptional modules associated with the multimorbidity in the Multi-Ethnic Study of Atherosclerosis (MESA) study. Here we examine whether these modules predict worsening multimorbidity over time. Transcriptomic profiles were determined in circulating monocytes from 1,264 MESA participants aged 55-94 (51% female, 53% minority). The multimorbidity index was defined as the number of prevalent diseases: cardiovascular disease, type-2 diabetes, hypertension, cancer, dementia, chronic kidney disease, chronic obstructive pulmonary disease, and hip fracture. The mean index at baseline was 1.0 (33%, 45%, and 22% with 0, 1, and 2-6 diseases respectively). At baseline, the index was associated with 5 co-expressed transcriptional modules (FDR< 0.05). During a 6-year follow-up, 449 individuals developed new morbidities. In Cox proportional hazards regression models, 4 (p< 0.05) of these 5 modules including those enriched for downregulation of apoptosis (RH=1.11 per SD increment, p=0.03) and upregulation of complement subcomponent C1q (RH=1.14, p=0.005) predicted incident morbid diseases after adjusting for age, sex, race/ethnicity, study site, and the baseline multimorbidity index. Persons having above the median expression of both modules developed an average of 0.63 new diseases, while those with both below the median developed an average of 0.40 new diseases. These two modules predicted increasing morbidities independently of one another and IL6 levels (p< 0.05). In conclusion, transcriptomic analysis of human immune cells provided evidence that decreased apoptosis and increased immune response predict the onset of a variety of age-related diseases. Whether targeting these pathways will change morbidity risk remains to be demonstrated.

Introduction: Visceral adipose tissue (VAT) has been associated with higher levels of atherosclerosis. Renal artery calcification (RAC) secondary to atherosclerosis has been found to be associated with hypertension and an increase in all-cause mortality. Hypothesis: There are significant associations between VAT area and density with the presence and extent of renal artery calcification. Methods: Within the Multi-Ethnic Study of Atherosclerosis (MESA) abdominal aortic calcification ancillary study, 1,978 participants from five of the six field centers around the US underwent abdominal CT imaging to measure VAT and RAC. Standardized questionnaires were used to obtain demographic and health history data. Blood samples were assayed for lipid, glucose, creatinine, and adipokine levels. Rate ratio regression was used to estimate prevalence ratios (PRs) for the presence of RAC, while linear regression was used to estimate linear coefficients for the severity of RAC among participants with RAC > 0. Results: Of the 1,978 participants, 1,196 participants had complete visceral adiposity and renal artery measurements. After controlling for sociodemographic variables, CVD risk factors, adipokine levels, and VAT density, VAT area was not associated with RAC presence (PR 1.02, 95% CI 0.89, 1.16, p = 0.80), while greater VAT density was borderline protective for RAC presence (PR 0.89, 95% CI 0.78, 1.02, p = 0.10) when controlling for the same factors and VAT area. 354 participants had RAC > 0 and were included in linear regression analyses assessing RAC severity. After controlling for sociodemographic variables, CVD risk factors, adipokine levels, and VAT density, VAT area was significantly associated with RAC severity (slope 63.32, 95% CI 11.84, 114.81, p = 0.02), while VAT density was not associated with RAC severity (slope 9.78, 95% CI -40.87, 60.44, p = 0.71). Conclusions: In this relatively large, multi-ethnic cohort of adults from five communities in the US, we have demonstrated that higher density VAT may be protective for RAC presence, while greater VAT area is significantly associated with RAC severity. While this is the first study examining the relationship between VAT and RAC, our results are consistent with previous studies describing associations between increased VAT area and decreased VAT density with outcomes including hypertension, hypercholesterolemia, and metabolic syndrome. Category: Subclinical Cardiovascular Disease

There are no circulating markers exclusive to cell senescence for clinical trials in middle-aged/older adults. In this study we evaluated T-cell expression of tumor suppressor protein p16INK4a and plasma senescence associated secretory proteins (SASP)-factors in the context of an 18-week randomized trial of caloric restriction (CR) compared to a weight stable Control. The analysis includes 55 middle-aged/older adults (75%Women; 33%African American; 57.6±5.8 years) with obesity and prediabetes. We measured mRNA expression of select senescence and apoptosis gene transcripts (p16INK4a, p21, BCL2L, BAK1) in peripheral blood CD3+ T-cells (quantitative-RT-PCR) and a panel of 27 plasma SASP proteins (Luminex/multiplex; ELISA). Weight loss in those randomized to CR was -10.8±0.9 kg compared to +0.5±0.9 kg in Control. Using mixed models, T-cell expression of senescence-biomarkers p16INK4a, p21, BCL-2L, and apoptosis-marker BAK1 were not different between CR and control at 18 weeks (time × treatment adjusted for age, race, and sex, all p>0.05). We explored associations between biomarkers with weight loss; moderate spearman correlations (rs=0.28 to 0.64) were observed between weight loss and change in plasma SASP-factors (Activin A, I-CAM, MMP1, PAI-1, TNF-RI, TNF-RII, VEGF, uPAR, p< 0.05 all), but not T-cell biomarker expression. We evaluated associations between biomarkers and found change in T-cell p16INK4a was associated with change in plasma SASP-factors, Fas (rs=0.51), osteopontin (rs=0.34), myeloperoxidase (rs=0.39), and MMP2 (rs=0.40) (CR+Control combined). Among middle-aged/older persons with obesity undergoing 18-weeks CR, changes in T cell p16INK4a expression were correlated with reductions in key SASP factors, and weight loss was associated with lower pro-inflammatory SASP profile.