Gut Microbiota and Blood Metabolites Related to Fiber Intake and Type 2 Diabetes.

BACKGROUND: Consistent evidence suggests diabetes-protective effects of dietary fiber intake. However, the underlying mechanisms, particularly the role of gut microbiota and host circulating metabolites, are not fully understood. We aimed to investigate gut microbiota and circulating metabolites associated with dietary fiber intake and their relationships with type 2 diabetes (T2D). METHODS: This study included up to 11 394 participants from the HCHS/SOL (Hispanic Community Health Study/Study of Latinos). Diet was assessed with two 24-hour dietary recalls at baseline. We examined associations of dietary fiber intake with gut microbiome measured by shotgun metagenomics (350 species/85 genera and 1958 enzymes; n=2992 at visit 2), serum metabolome measured by untargeted metabolomics (624 metabolites; n=6198 at baseline), and associations between fiber-related gut bacteria and metabolites (n=804 at visit 2). We examined prospective associations of serum microbial-associated metabolites (n=3579 at baseline) with incident T2D over 6 years. RESULTS: We identified multiple bacterial genera, species, and related enzymes associated with fiber intake. Several bacteria (eg, Butyrivibrio, Faecalibacterium) and enzymes involved in fiber degradation (eg, xylanase EC3.2.1.156) were positively associated with fiber intake, inversely associated with prevalent T2D, and favorably associated with T2D-related metabolic traits. We identified 159 metabolites associated with fiber intake, 47 of which were associated with incident T2D. We identified 18 of these 47 metabolites associated with the identified fiber-related bacteria, including several microbial metabolites (eg, indolepropionate and 3-phenylpropionate) inversely associated with the risk of T2D. Both Butyrivibrio and Faecalibacterium were associated with these favorable metabolites. The associations of fiber-related bacteria, especially Faecalibacterium and Butyrivibrio, with T2D were attenuated after further adjustment for these microbial metabolites. CONCLUSIONS: Among United States Hispanics/Latinos, dietary fiber intake was associated with favorable profiles of gut microbiota and circulating metabolites for T2D. These findings advance our understanding of the role of gut microbiota and microbial metabolites in the relationship between diet and T2D.

Epigenetic-based age acceleration in a representative sample of older Americans: Associations with aging-related morbidity and mortality.

Biomarkers developed from DNA methylation (DNAm) data are of growing interest as predictors of health outcomes and mortality in older populations. However, it is unknown how epigenetic aging fits within the context of known socioeconomic and behavioral associations with aging-related health outcomes in a large, population-based, and diverse sample. This study uses data from a representative, panel study of US older adults to examine the relationship between DNAm-based age acceleration measures in the prediction of cross-sectional and longitudinal health outcomes and mortality. We examine whether recent improvements to these scores, using principal component (PC)-based measures designed to remove some of the technical noise and unreliability in measurement, improve the predictive capability of these measures. We also examine how well DNAm-based measures perform against well-known predictors of health outcomes such as demographics, SES, and health behaviors. In our sample, age acceleration calculated using "second and third generation clocks," PhenoAge, GrimAge, and DunedinPACE, is consistently a significant predictor of health outcomes including cross-sectional cognitive dysfunction, functional limitations and chronic conditions assessed 2 y after DNAm measurement, and 4-y mortality. PC-based epigenetic age acceleration measures do not significantly change the relationship of DNAm-based age acceleration measures to health outcomes or mortality compared to earlier versions of these measures. While the usefulness of DNAm-based age acceleration as a predictor of later life health outcomes is quite clear, other factors such as demographics, SES, mental health, and health behaviors remain equally, if not more robust, predictors of later life outcomes.

Dietary Acculturation Is Associated With Altered Gut Microbiome, Circulating Metabolites, and Cardiovascular Disease Risk in US Hispanics and Latinos: Results From HCHS/SOL.

BACKGROUND: Dietary acculturation, or adoption of dominant culture diet by migrant groups, influences human health. We aimed to examine dietary acculturation and its relationships with cardiovascular disease (CVD), gut microbiota, and blood metabolites among US Hispanic and Latino adults. METHODS: In the HCHS/SOL (Hispanic Community Health Study/Study of Latinos), US exposure was defined by years in the United States (50 states and Washington, DC) and US nativity. A dietary acculturation pattern was derived from 14 172 participants with two 24-hour dietary recalls at baseline (2008-2011) using least absolute shrinkage and selection operator regression, with food groups as predictors of US exposure. We evaluated associations of dietary acculturation with incident CVD across ≈7 years of follow-up (n=211/14 172 cases/total) and gut microbiota (n=2349; visit 2, 2014 to 2017). Serum metabolites associated with both dietary acculturation-related gut microbiota (n=694) and incident CVD (n=108/5256 cases/total) were used as proxy measures to assess the association of diet-related gut microbiome with incident CVD. RESULTS: We identified an empirical US-oriented dietary acculturation score that increased with US exposure. Higher dietary acculturation score was associated with higher risk of incident CVD (hazard ratio per SD, 1.33 [95% CI, 1.13-1.57]), adjusted for sociodemographic, lifestyle, and clinical factors. Sixty-nine microbial species (17 enriched from diverse species, 52 depleted mainly from fiber-utilizing Clostridia and Prevotella species) were associated with dietary acculturation, driven by lower intakes of whole grains, beans, and fruits and higher intakes of refined grains. Twenty-five metabolites, involved predominantly in fatty acid and glycerophospholipid metabolism (eg, branched-chain 14:0 dicarboxylic acid** and glycerophosphoethanolamine), were associated with both diet acculturation-related gut microbiota and incident CVD. Proxy association analysis based on these metabolites suggested a positive relationship between diet acculturation-related microbiome and risk of CVD (r=0.70, P<0.001). CONCLUSIONS: Among US Hispanic and Latino adults, greater dietary acculturation was associated with elevated CVD risk, possibly through alterations in gut microbiota and related metabolites. Diet and microbiota-targeted interventions may offer opportunities to mitigate CVD burdens of dietary acculturation.

Proteomic Biomarkers of Quantitative Interstitial Abnormalities in COPDGene and CARDIA Lung Study.

Rationale: Quantitative interstitial abnormalities (QIAs) are early measures of lung injury automatically detected on chest computed tomography scans. QIAs are associated with impaired respiratory health and share features with advanced lung diseases, but their biological underpinnings are not well understood. Objectives: To identify novel protein biomarkers of QIAs using high-throughput plasma proteomic panels within two multicenter cohorts. Methods: We measured the plasma proteomics of 4,383 participants in an older, ever-smoker cohort (COPDGene [Genetic Epidemiology of Chronic Obstructive Pulmonary Disease]) and 2,925 participants in a younger population cohort (CARDIA [Coronary Artery Disease Risk in Young Adults]) using the SomaLogic SomaScan assays. We measured QIAs using a local density histogram method. We assessed the associations between proteomic biomarker concentrations and QIAs using multivariable linear regression models adjusted for age, sex, body mass index, smoking status, and study center (Benjamini-Hochberg false discovery rate-corrected P ⩽ 0.05). Measurements and Main Results: In total, 852 proteins were significantly associated with QIAs in COPDGene and 185 in CARDIA. Of the 144 proteins that overlapped between COPDGene and CARDIA, all but one shared directionalities and magnitudes. These proteins were enriched for 49 Gene Ontology pathways, including biological processes in inflammatory response, cell adhesion, immune response, ERK1/2 regulation, and signaling; cellular components in extracellular regions; and molecular functions including calcium ion and heparin binding. Conclusions: We identified the proteomic biomarkers of QIAs in an older, smoking population with a higher prevalence of pulmonary disease and in a younger, healthier community cohort. These proteomics features may be markers of early precursors of advanced lung diseases.

Proteomic Risk Score of Increased Respiratory Susceptibility: A Multi-Cohort Study.

RATIONALE: Accelerated decline in lung function is associated with incident COPD, hospitalizations and death. However, identifying this trajectory with longitudinal spirometry measurements is challenging in clinical practice. OBJECTIVE: To determine whether a proteomic risk score trained on accelerated decline in lung function can assess risk of future respiratory disease and mortality. METHODS: In CARDIA, a population-based cohort starting in young adulthood, longitudinal measurements of FEV1 percent predicted (up to six timepoints over 30 years) were used to identify accelerated and normal decline trajectories. Protein aptamers associated with an accelerated decline trajectory were identified with multivariable logistic regression followed by LASSO regression. The proteomic respiratory susceptibility score was derived based on these circulating proteins and applied to the UK Biobank and COPDGene studies to examine associations with future respiratory morbidity and mortality. MEASUREMENTS AND RESULTS: Higher susceptibility score was independently associated with all-cause mortality (UKBB: HR 1.56, 95%CI 1.50-1.61; COPDGene: HR 1.75, 95%CI 1.63-1.88), respiratory mortality (UKBB: HR 2.39, 95% CI 2.16-2.64; COPDGene: HR 1.83, 95%CI 1.33-2.51), incident COPD (UKBB: HR 1.84, 95%CI 1.71-1.98), incident respiratory exacerbation (COPDGene: OR 1.11, 95%CI 1.03-1.20), and incident exacerbation requiring hospitalization (COPDGene: OR 1.18, 95%CI 1.08-1.28). CONCLUSIONS: A proteomic signature of increased respiratory susceptibility identifies people at risk of respiratory death, incident COPD, and respiratory exacerbations. This susceptibility score is comprised of proteins with well-known and novel associations with lung health and holds promise for the early detection of lung disease without requiring years of spirometry measurements.

Development, characterization, and replication of proteomic aging clocks: Analysis of 2 population-based cohorts.

BACKGROUND: Biological age may be estimated by proteomic aging clocks (PACs). Previous published PACs were constructed either in smaller studies or mainly in white individuals, and they used proteomic measures from only one-time point. In this study, we created de novo PACs and compared their performance to published PACs at 2 different time points in the Atherosclerosis Risk in Communities (ARIC) study of white and black participants (around 75% white and 25% black). MEDTHODS AND FINDINGS: A total of 4,712 plasma proteins were measured using SomaScan in blood samples collected in 1990 to 1992 from 11,761 midlife participants (aged 46 to 70 years) and in 2011 to 2013 from 5,183 late-life participants (aged 66 to 90 years). The de novo ARIC PACs were constructed by training them against chronological age using elastic net regression in two-thirds of healthy participants in midlife and late life and validated in the remaining one-third of healthy participants at the corresponding time point. We also computed 3 published PACs. We estimated age acceleration for each PAC as residuals after regressing each PAC on chronological age. We also calculated the change in age acceleration from midlife to late life. We examined the associations of age acceleration and change in age acceleration with mortality through 2019 from all-cause, cardiovascular disease (CVD), cancer, and lower respiratory disease (LRD) using Cox proportional hazards regression in participants (irrespective of health) after excluding the training set. The model was adjusted for chronological age, smoking, body mass index (BMI), and other confounders. We externally validated the midlife PAC using the Multi-Ethnic Study of Atherosclerosis (MESA) Exam 1 data. The ARIC PACs had a slightly stronger correlation with chronological age than published PACs in healthy participants at each time point. Associations with mortality were similar for the ARIC PACs and published PACs. For late-life and midlife age acceleration for the ARIC PACs, respectively, hazard ratios (HRs) per 1 standard deviation were 1.65 and 1.38 (both p < 0.001) for all-cause mortality, 1.37 and 1.20 (both p < 0.001) for CVD mortality, 1.21 (p = 0.028) and 1.04 (p = 0.280) for cancer mortality, and 1.46 and 1.68 (both p < 0.001) for LRD mortality. For the change in age acceleration, HRs for all-cause, CVD, and LRD mortality were comparable to the HRs for late-life age acceleration. The association between the change in age acceleration and cancer mortality was not significant. The external validation of the midlife PAC in MESA showed significant associations with mortality, as observed for midlife participants in ARIC. The main limitation is that our PACs were constructed in midlife and late-life participants. It is unknown whether these PACs could be applied to young individuals. CONCLUSIONS: In this longitudinal study, we found that the ARIC PACs and published PACs were similarly associated with an increased risk of mortality. These findings suggested that PACs show promise as biomarkers of biological age. PACs may be serve as tools to predict mortality and evaluate the effect of anti-aging lifestyle and therapeutic interventions.

Changes in Alzheimer Disease Blood Biomarkers and Associations With Incident All-Cause Dementia.

Importance: Plasma biomarkers show promise for identifying Alzheimer disease (AD) neuropathology and neurodegeneration, but additional examination among diverse populations and throughout the life course is needed. Objective: To assess temporal plasma biomarker changes and their association with all-cause dementia, overall and among subgroups of community-dwelling adults. Design, Setting, and Participants: In 1525 participants from the US-based Atherosclerosis Risk in Communities (ARIC) study, plasma biomarkers were measured using stored specimens collected in midlife (1993-1995, mean age 58.3 years) and late life (2011-2013, mean age 76.0 years; followed up to 2016-2019, mean age 80.7 years). Midlife risk factors (hypertension, diabetes, lipids, coronary heart disease, cigarette use, and physical activity) were assessed for their associations with change in plasma biomarkers over time. The associations of biomarkers with incident all-cause dementia were evaluated in a subpopulation (n = 1339) who were dementia-free in 2011-2013 and had biomarker measurements in 1993-1995 and 2011-2013. Exposure: Plasma biomarkers of amyloid-ß 42 to amyloid-ß 40 (Aß42:Aß40) ratio, phosphorylated tau at threonine 181 (p-tau181), neurofilament light (NfL), and glial fibrillary acidic protein (GFAP) were measured using the Quanterix Simoa platform. Main Outcomes and Measures: Incident all-cause dementia was ascertained from January 1, 2012, through December 31, 2019, from neuropsychological assessments, semiannual participant or informant contact, and medical record surveillance. Results: Among 1525 participants (mean age, 58.3 [SD, 5.1] years), 914 participants (59.9%) were women, and 394 participants (25.8%) were Black. A total of 252 participants (16.5%) developed dementia. Decreasing Aß42:Aß40 ratio and increasing p-tau181, NfL, and GFAP were observed from midlife to late life, with more rapid biomarker changes among participants carrying the apolipoprotein E epsilon 4 (APOEε4) allele. Midlife hypertension was associated with a 0.15-SD faster NfL increase and a 0.08-SD faster GFAP increase per decade; estimates for midlife diabetes were a 0.11-SD faster for NfL and 0.15-SD faster for GFAP. Only AD-specific biomarkers in midlife demonstrated long-term associations with late-life dementia (hazard ratio per SD lower Aß42:Aß40 ratio, 1.11; 95% CI, 1.02-1.21; per SD higher p-tau181, 1.15; 95% CI, 1.06-1.25). All plasma biomarkers in late life had statistically significant associations with late-life dementia, with NfL demonstrating the largest association (1.92; 95% CI, 1.72-2.14). Conclusions and Relevance: Plasma biomarkers of AD neuropathology, neuronal injury, and astrogliosis increase with age and are associated with known dementia risk factors. AD-specific biomarkers' association with dementia starts in midlife whereas late-life measures of AD, neuronal injury, and astrogliosis biomarkers are all associated with dementia.

Whole genome-wide sequence analysis of long-lived families (Long-Life Family Study) identifies MTUS2 gene associated with late-onset Alzheimer's disease.

INTRODUCTION: Late-onset Alzheimer's disease (LOAD) has a strong genetic component. Participants in Long-Life Family Study (LLFS) exhibit delayed onset of dementia, offering a unique opportunity to investigate LOAD genetics. METHODS: We conducted a whole genome sequence analysis of 3475 LLFS members. Genetic associations were examined in six independent studies (N = 14,260) with a wide range of LOAD risk. Association analysis in a sub-sample of the LLFS cohort (N = 1739) evaluated the association of LOAD variants with beta amyloid (Aß) levels. RESULTS: We identified several single nucleotide polymorphisms (SNPs) in tight linkage disequilibrium within the MTUS2 gene associated with LOAD (rs73154407, p = 7.6 × 10-9). Association of MTUS2 variants with LOAD was observed in the five independent studies and was significantly stronger within high levels of Aß42/40 ratio compared to lower amyloid. DISCUSSION: MTUS2 encodes a microtubule associated protein implicated in the development and function of the nervous system, making it a plausible candidate to investigate LOAD biology. HIGHLIGHTS: Long-Life Family Study (LLFS) families may harbor late onset Alzheimer's dementia (LOAD) variants. LLFS whole genome sequence analysis identified MTUS2 gene variants associated with LOAD. The observed LLFS variants generalized to cohorts with wide range of LOAD risk. The association of MTUS2 with LOAD was stronger within high levels of beta amyloid. Our results provide evidence for MTUS2 gene as a novel LOAD candidate locus.

Connections between reproductive health and cognitive aging among women enrolled in the HCHS/SOL and SOL-INCA.

INTRODUCTION: Reproductive health history may contribute to cognitive aging and risk for Alzheimer's disease, but this is understudied among Hispanic/Latina women. METHODS: Participants included 2126 Hispanic/Latina postmenopausal women (44 to 75 years) from the Study of Latinos-Investigation of Neurocognitive Aging. Survey linear regressions separately modeled the associations between reproductive health measures (age at menarche, history of oral contraceptive use, number of pregnancies, number of live births, age at menopause, female hormone use at Visit 1, and reproductive span) with cognitive outcomes at Visit 2 (performance, 7-year change, and mild cognitive impairment [MCI] prevalence). RESULTS: Younger age at menarche, oral contraceptive use, lower pregnancies, lower live births, and older age at menopause were associated with better cognitive performance. Older age at menarche was protective against cognitive change. Hormone use was linked to lower MCI prevalence. DISCUSSION: Several aspects of reproductive health appear to impact cognitive aging among Hispanic/Latina women.

Accelerated Aging in Cancer Survivors: Cellular Senescence, Frailty, and Possible Opportunities for Interventions.

The population of cancer survivors has markedly increased due to the rapid improvements in cancer treatment. However, cancer survivors experience accelerated aging, which leads to chronic diseases and other age-related conditions, such as frailty. Those conditions may persist years after cancer diagnosis and treatment. Cellular senescence, a hallmark of aging, is one of the mechanisms that contribute to accelerated aging in cancer survivors. Several aging measures, including measures based on clinical markers and biomarkers, have been proposed to estimate the aging process, and some of them have shown associations with mortality and frailty in cancer survivors. Several anti-aging interventions, including lifestyle changes and anti-aging drugs, have been proposed. Future research, particularly in large-scale studies, is needed to determine the efficiency of these aging measures and anti-aging interventions before considering their application in clinics. This review focuses on the mechanisms of cellular senescence and accelerated aging in cancer survivors, assessment of the aging process using clinical markers and biomarkers, and the high prevalence of frailty in that population, as well as possible opportunities for anti-aging interventions. A deeper understanding of aging measures and anti-aging interventions in cancer survivors will contribute to the development of effective strategies to mitigate accelerated aging in cancer survivors and improve their quality of life.

Association between Circulating T Cells and the Gut Microbiome in Healthy Individuals: Findings from a Pilot Study.

Though the microbiome's impact on immune system homeostasis is well documented, the effect of circulating T cells on the gut microbiome remains unexamined. We analyzed data from 50 healthy volunteers in a pilot trial of aspirin, using immunophenotyping and 16S rRNA sequencing to evaluate the effect of baseline T cells on microbiome changes over 6 weeks. We employed an unsupervised sparse canonical correlation analysis (sCCA) and used multivariable linear regression models to evaluate the association between selected T cell subsets and selected bacterial genera after adjusting for covariates. In the cross-sectional analysis, percentages of naïve CD4+ T cells were positively associated with a relative abundance of Intestinimonas, and the percentage of activated CD8+ T cells was inversely associated with Cellulosibacter. In the longitudinal analysis, the baseline percentages of naïve CD4+ T cells and activated CD4+ T cells were inversely associated with a 6-week change in the relative abundance of Clostridium_XlVb and Anaerovorax, respectively. The baseline percentage of terminal effector CD4+ T cells was positively associated with the change in Flavonifractor. Notably, the microbiome taxa associated with T cell subsets exclusively belonged to the Bacillota phylum. These findings can guide future experimental studies focusing on the role of T cells in impacting gut microbiome homeostasis.

Nutritional Blood Concentration Biomarkers in the Hispanic Community Health Study/Study of Latinos: Measurement Characteristics and Power.

Measurement error is a major issue in self-reported diet that can distort diet-disease relationships. Use of blood concentration biomarkers has the potential to mitigate the subjective bias inherent in self-reporting. As part of the Hispanic Community Health Study/Study of Latinos (HCHS/SOL) baseline visit (2008-2011), self-reported information on diet was collected from all participants (n = 16,415). The HCHS/SOL also included annual telephone follow-up, as well as a second (2014-2017) and third (2020-2023) clinic visit. Blood concentration biomarkers for carotenoids, tocopherols, retinol, vitamin B12, and folate were measured in a subset of participants (n = 476) as part of the Study of Latinos: Nutrition and Physical Activity Assessment Study (SOLNAS) (2010-2012). We examined the relationships among biomarker levels, self-reported intake, Hispanic/Latino background (Central American, Cuban, Dominican, Mexican, Puerto Rican, or South American), and other participant characteristics in this diverse cohort. We built regression calibration-based prediction equations for 10 nutritional biomarkers and used a simulation to study the power of detecting a diet-disease association in a multivariable Cox model using a predicted concentration level. Good statistical power was observed for some nutrients with high prediction model R2 values, but further research is needed to understand how best to realize the potential of these dietary biomarkers. This study provides a comprehensive examination of several nutritional biomarkers within the HCHS/SOL, characterizing their associations with subject characteristics and the influence of the measurement characteristics on the power to detect associations with health outcomes.

Childhood and Life-Course Socioeconomic Position and Cognitive Function in the Adult Population of the Hispanic Community Health Study/Study of Latinos.

The Hispanic/Latino population experiences socioeconomic adversities across the lifespan and is at greater risk of cognitive impairment, yet little is known about the role of life-course socioeconomic position (SEP) in cognitive function in this population. Using baseline data (2008-2011) from adults (aged 45-74 years) of the Hispanic Community Health Study/Study of Latinos, we assessed the association between childhood SEP and socioeconomic mobility with cognitive function, and whether this association was mediated by midlife SEP. Childhood SEP was assessed using parental education. An index combining participants' education and household income represented midlife SEP. Socioeconomic mobility was categorized as stable low, downward or upward mobility, and stable high-SEP. Cognitive function measures were modeled using survey linear regression with inverse-probability weighting, accounting for covariates. We used mediation analysis to estimate the indirect effect of childhood SEP on cognition through midlife SEP. High childhood SEP was associated with global cognition in adulthood (coefficient for parental education beyond high school vs. less than high school = 0.26, 95% confidence interval: 0.15, 0.37). This association was partially mediated through midlife SEP (indirect effect coefficient = 0.16, 95% confidence interval: 0.15, 0.18). Low SEP through the life course was associated with the lowest cognitive function. This study provides evidence that life-course SEP influences cognitive performance in adulthood.

Explainable variational autoencoder (E-VAE) model using genome-wide SNPs to predict dementia.

OBJECTIVE: Alzheimer's disease (AD) and AD related dementias (ADRD) are complex multifactorial neurodegenerative diseases. The associations between genetic variants obtained from genome wide association studies (GWAS) are the most widely available and well documented variants associated with ADRD. Application of deep learning methods to analyze large scale GWAS data may be a powerful approach to elucidate the biological mechanisms in ADRD compared to penalized regression models that may lead to over-fitting. METHODS: We developed a deep learning frame work explainable variational autoencoder (E-VAE) classifier model using genotype (GWAS SNPs = 5474) data from 2714 study participants in the Health and Retirement Study (HRS) to classify ADRD. We validated the generalizability of this model among 234 participants in the Religious Orders Study and Memory and Aging Project (ROSMAP). Utilizing a linear decoder approach we have extracted the weights associated with latent features for biological interpretation. RESULTS: We obtained a predictive accuracy of 0.71 (95 % CI [0.59, 0.84]) with an AUC of 0.69 in the HRS test dataset and got an accuracy of 0.62 (95 % CI [0.56, 0.68]) with an AUC of 0.63 in the ROSMAP dataset. CONCLUSION: This is the first study showing the generalizability of a deep learning prediction model for dementia using genetic variants in an independent cohort. The latent features identified using E-VAE can help us understand the biology of AD/ ADRD and better characterize disease status.

Host and gut microbial tryptophan metabolism and type 2 diabetes: an integrative analysis of host genetics, diet, gut microbiome and circulating metabolites in cohort studies.

OBJECTIVE: Tryptophan can be catabolised to various metabolites through host kynurenine and microbial indole pathways. We aimed to examine relationships of host and microbial tryptophan metabolites with incident type 2 diabetes (T2D), host genetics, diet and gut microbiota. METHOD: We analysed associations between circulating levels of 11 tryptophan metabolites and incident T2D in 9180 participants of diverse racial/ethnic backgrounds from five cohorts. We examined host genome-wide variants, dietary intake and gut microbiome associated with these metabolites. RESULTS: Tryptophan, four kynurenine-pathway metabolites (kynurenine, kynurenate, xanthurenate and quinolinate) and indolelactate were positively associated with T2D risk, while indolepropionate was inversely associated with T2D risk. We identified multiple host genetic variants, dietary factors, gut bacteria and their potential interplay associated with these T2D-relaetd metabolites. Intakes of fibre-rich foods, but not protein/tryptophan-rich foods, were the dietary factors most strongly associated with tryptophan metabolites. The fibre-indolepropionate association was partially explained by indolepropionate-associated gut bacteria, mostly fibre-using Firmicutes. We identified a novel association between a host functional LCT variant (determining lactase persistence) and serum indolepropionate, which might be related to a host gene-diet interaction on gut Bifidobacterium, a probiotic bacterium significantly associated with indolepropionate independent of other fibre-related bacteria. Higher milk intake was associated with higher levels of gut Bifidobacterium and serum indolepropionate only among genetically lactase non-persistent individuals. CONCLUSION: Higher milk intake among lactase non-persistent individuals, and higher fibre intake were associated with a favourable profile of circulating tryptophan metabolites for T2D, potentially through the host-microbial cross-talk shifting tryptophan metabolism toward gut microbial indolepropionate production.

Seroprevalence and Determinants of Helicobacter pylori Infection in the Hispanic Community Health Study/Study of Latinos.

BACKGROUND & AIMS: Helicobacter pylori infection is the primary known risk factor for gastric cancer. Despite the global decline in H. pylori prevalence, this infection remains a major public health concern in developing areas, including Latin America. Our study aimed to determine H. pylori seroprevalence and identified its determinants among Hispanics/Latinos living in the United States (U.S.). METHODS: The Hispanic Community Health Study/Study of Latinos (HCHS/SOL) is a population-based sample of self-identified Hispanics/Latinos (n = 16,144) in four U.S. communities, aged 18 to 74 years, recruited from randomly selected households using a stratified two-stage area probability sample design based on sampling households within sampled census block groups weighted for differential response rates. Anti-H. pylori immunoglobulin G antibodies were measured by an enzyme-linked immunosorbent assay using plasma samples. We calculated adjusted seroprevalence (i.e., predicted margins) from multivariable logistic regression models. RESULTS: The overall weighted H. pylori seroprevalence was 57% among HCHS/SOL participants, with 38% and 62% seropositivity among U.S.-born and non-U.S.-born individuals, respectively. Age-adjusted prevalence varied by self-reported Hispanic/Latino background, ranging from 47% in Puerto Rican to 72% in Central American backgrounds. Adjusted H. pylori seroprevalence was higher in the following groups: older age, male sex, lower education, non-U.S. born status, smoking, greater number of missing teeth, fewer doctor visits, lower ferritin level, and hepatitis A seropositivity. CONCLUSIONS: H. pylori seroprevalence in Hispanics/Latinos remains high and differed significantly by Hispanic/Latino background. H. pylori seropositivity is strongly associated with poor socioeconomic conditions. These findings highlight the ongoing importance of this bacterial infection in the U.S.

Cross sectional association between cytomegalovirus seropositivity, inflammation and cognitive impairment in elderly cancer survivors.

PURPOSE: The higher prevalence of cognitive impairment/ dementia among cancer survivors is likely multifactorial. Since both exposures to cytomegalovirus (CMV) and inflammation are common among elderly cancer survivors, we evaluated their contribution towards dementia. METHODS: Data from 1387 cancer survivors and 7004 participants without cancer in the 2016 wave of the Health and Retirement Study (HRS) was used in this study. Two inflammatory biomarkers, C-reactive protein (CRP) and neutrophil-lymphocyte ratio (NLR), were used to create an inflammation score. We used survey logistic regression adjusted for survey design parameters. RESULTS: CMV seropositivity was not associated with cognitive impairment among cancer survivors (p = 0.2). In addition, inflammation was associated with elevated odds of cognitive impairment (OR = 2.2, 95% CI [1.2, 4.2]). Cancer survivors who were both CMV seropositive and had increased inflammation had the highest odds of cognitive impairment compared to those who were CMV seronegative and had low inflammation (OR = 3.8, 95% CI [1.5, 9.4]). The stratified analysis among cancer survivors showed this association was seen only among cancer survivors in whom the cancer was diagnosed within three years of measurement of inflammation score and CMV serostatus (OR = 18.5; 95% CI [6.1, 56.1]). CONCLUSION: The CMV seropositivity and high inflammation was associated with higher cognitive impairment among cancer survivors. The stronger associations seen among cancer survivors diagnosed within the last three years suggest that strategies to reduce CMV activation and inflammation during or immediately after cancer treatment may be important in reducing the prevalence of cognitive impairment/ dementia among cancer survivors.

Progressive reduction in circulating levels of carotenoids and other micronutrients in patients with chronic pancreatitis.

BACKGROUND: Although micronutrients modulate immunity and inflammation, it remains elusive whether they are implicated in the development and progression of chronic pancreatitis (CP). This study aimed to investigate differences in the circulating levels of selected carotenoids and vitamins between CP and controls and trends in the levels of these micronutrients across controls, early CP, and definite CP. METHODS: Demographic and lifestyle data were extracted from medical records for 53 patients with CP (13 early and 38 definite) and obtained using a questionnaire for 52 controls. Plasma ß-carotene, lycopene, cryptoxanthin, zeaxanthin, and α-tocopherol and serum 25(OH)D, folate, IL-6, TNF-α, and MCP-1 were measured with state-of-the-art methods. RESULTS: The levels of all micronutrients (except folate) were significantly lower in CP than in controls. There was a progressive decrease in the levels of these micronutrients across controls, early CP, and definite CP (all p values for trend: ≤0.0012); e.g., plasma lycopene was 36.6, 21.5, and 14.5 µg/dL for controls, early CP, and definite CP, respectively. After adjustment for confounders, there were strong, inverse associations between the levels of all micronutrients (except folate) and CP (e.g., OR (95% CI) for ≥ median vs.

Sex-Specific Associations of Iron-Anemia Status With Hemoglobin A1C Levels Among Hispanics/Latinos Without Self-Reported Diabetes Mellitus: The Hispanic Community Health Study/Study of Latinos.

OBJECTIVE: The objective of this study was to examine the sex-specific associations of mutually exclusive iron-anemia status categories with hemoglobin A1C (HbA1C) levels among U.S. Hispanics/Latinos without self-reported diabetes mellitus. METHODS: Baseline cross-sectional data (7247 women and 4904 men without self-reported diabetes mellitus) from the Hispanic Community Health Study/Study of Latinos were analyzed. Per the American Diabetes Association's defined criteria, based on HbA1C levels, the participants were categorized as having normoglycemia, prediabetes, or probable diabetes mellitus. The iron-anemia status categories were as follows: no anemia and no iron deficiency (reference), iron deficiency, iron deficiency anemia (IDA), and non-iron deficiency anemia (non-IDA). Survey multinomial logistic regression models were used to examine the sex-specific associations of iron-anemia status with HbA1C levels after adjusting for sociodemographic, lifestyle, and clinical factors. RESULTS: The age-standardized prevalence of iron-anemia status categories differed by sex. Compared with those with no anemia and no iron deficiency and normoglycemia, women with IDA had higher odds of having prediabetes (odds ratio [OR], 2.18; 95% CI, 1.64-2.89) and probable diabetes mellitus (OR, 3.59; 95% CI, 1.62-7.99) based on HbA1C levels; men with non-IDA had higher odds of having probable diabetes mellitus (OR, 2.97; 95% CI, 1.13-7.78) based on HbA1C levels. All other associations did not reach statistical significance. CONCLUSION: Among U.S. Hispanics/Latinos without self-reported diabetes mellitus, the age-standardized prevalence of iron deficiency, IDA, and non-IDA is high and varies by sex. Women with IDA had higher odds of having prediabetes and probable diabetes mellitus, defined based on HbA1C levels. Men with non-IDA had higher odds of having probable diabetes mellitus, defined based on HbA1C levels. Iron-anemia status should be considered while interpreting elevated HbA1C levels among U.S. Hispanics/Latinos without self-reported diabetes mellitus.

Evaluation of T-cell aging-related immune phenotypes in the context of biological aging and multimorbidity in the Health and Retirement Study.

BACKGROUND: Cellular changes in adaptive immune system accompany the process of aging and contribute to an aging-related immune phenotype (ARIP) characterized by decrease in naïve T-cells (TN) and increase in memory T-cells (TM). A population-representative marker of ARIP and its associations with biological aging and age-related chronic conditions have not been studied previously. METHODS: We developed two ARIP indicators based on well understood age-related changes in T cell distribution: TN/(TCM (Central Memory) + TEM (Effector Memory) + TEFF (Effector)) (referred as TN/TM) in CD4 + and CD8 + T-cells. We compared them with existing ARIP measures including CD4/CD8 ratio and CD8 + TN cells by evaluating associations with chronological age and the Klemera Doubal measure of biological age (measured in years) using linear regression, multimorbidity using multinomial logistic regression and two-year mortality using logistic regression. RESULTS: CD8 + TN and CD8 + TN/TM had the strongest inverse association with chronological age (beta estimates: -3.41 and -3.61 respectively; p-value < 0.0001) after adjustment for sex, race/ethnicity and CMV status. CD4 + TN/TM and CD4 + TN had the strongest inverse association with biological age (ß = -0.23; p = 0.003 and ß = -0.24; p = 0.004 respectively) after adjustment for age, sex, race/ethnicity and CMV serostatus. CD4/CD8 ratio was not associated with chronological age or biological age. CD4 + TN/TM and CD4 + TN was inversely associated with multimorbidity. For CD4 + TN/TM, people with 2 chronic conditions had an odds ratio of for 0.74 (95%CI: 0.63-0.86 p = 0.0003) compared to those without any chronic conditions while those with 3 chronic conditions had an odds ratio of 0.75 (95% CI: 0.63-0.90; p = 0.003) after adjustment for age, sex, race/ethnicity, CMV serostatus, smoking, and BMI. The results for the CD4 + TN subset were very similar to the associations seen with the CD4 + TN/TM. CD4 + TN/TM and CD4 + TN were both associated with two-year mortality (OR = 0.80 (95% CI: 0.67-0.95; p = 0.01) and 0.81 (0.70-0.94; p = 0.01), respectively). CONCLUSION: CD4 + TN/TM and CD4 + TN had a stronger association with biological age, age-related morbidity and mortality compared to other ARIP measures. Future longitudinal studies are needed to evaluate the utility of the CD4 + subsets in predicting the risk of aging-related outcomes.