Epigenetic Age Acceleration and Cognitive Function in African American Adults in Midlife: The Atherosclerosis Risk in Communities Study.
ABSTRACT: Methylation levels measured at defined sites across the genome have recently been shown to be correlated with an individual's chronological age. Age acceleration, or the difference between age estimated from DNA methylation status and chronological age, has been proposed as a novel biomarker of aging. In this study, the cross-sectional association between two different measures of age acceleration and cognitive function was investigated using whole blood samples from 2,157 African American participants 47-70 years of age in the population-based Atherosclerosis Risk in Communities (ARIC) Study. Cognition was evaluated using three domain-specific tests. A significant inverse association between a 1-year increase in age acceleration calculated using a blood-based age predictor and scores on the Word Fluency Test was found using a general linear model adjusted for chronological age, gender, and years of education (? = -0.140 words; p = .001) and after adding other potential confounding variables (? = -0.104 words, p = .023). The results were replicated in 1,670 European participants in the Generation Scotland: Scottish Family Health Study (fully adjusted model: ? = -0.199 words; p = .034). A significant association was also identified in a trans-ethnic meta-analysis across cohorts that included an additional 708 European American ARIC study participants (fully adjusted model: ? = -0.110 words, p = .003). There were no associations found using an estimate of age acceleration derived from multiple tissues. These findings provide evidence that age acceleration is a correlate of performance on a test of verbal fluency in middle-aged adults.
Project description:Background:Recently, epigenetic age acceleration-or older epigenetic age in comparison to chronological age-has been robustly associated with mortality and various morbidities. However, accelerated epigenetic aging has not been widely investigated in relation to inflammatory or metabolic markers, including postprandial lipids. Methods:We estimated measures of epigenetic age acceleration in 830 Caucasian participants from the Genetics Of Lipid Lowering Drugs and diet Network (GOLDN) considering two epigenetic age calculations based on differing sets of 5'-Cytosine-phosphate-guanine-3' genomic site, derived from the Horvath and Hannum DNA methylation age calculators, respectively. GOLDN participants underwent a standardized high-fat meal challenge after fasting for at least 8 h followed by timed blood draws, the last being 6 h postmeal. We used adjusted linear mixed models to examine the association of the epigenetic age acceleration estimate with fasting and postprandial (0- and 6-h time points) low-density lipoprotein (LDL), high-density lipoprotein (HDL), and triglyceride (TG) levels as well as five fasting inflammatory markers plus adiponectin. Results:Both DNA methylation age estimates were highly correlated with chronological age (r?>?0.90). We found that the Horvath and Hannum measures of epigenetic age acceleration were moderately correlated (r?=?0.50). The regression models revealed that the Horvath age acceleration measure exhibited marginal associations with increased postprandial HDL (p?=?0.05), increased postprandial total cholesterol (p?=?0.06), and decreased soluble interleukin 2 receptor subunit alpha (IL2sR?, p?=?0.02). The Hannum measure of epigenetic age acceleration was inversely associated with fasting HDL (p?=?0.02) and positively associated with postprandial TG (p?=?0.02), interleukin-6 (IL6, p?=?0.007), C-reactive protein (C-reactive protein, p?=?0.0001), and tumor necrosis factor alpha (TNF?, p?=?0.0001). Overall, the observed effect sizes were small and the association of the Hannum residual with inflammatory markers was attenuated by adjustment for estimated T cell type percentages. Conclusions:Our study demonstrates that epigenetic age acceleration in blood relates to inflammatory biomarkers and certain lipid classes in Caucasian individuals of the GOLDN study. Future studies should consider epigenetic age acceleration in other tissues and extend the analysis to other ethnic groups.
Project description:Background:Animal fluency is a widely used task to assess people with Alzheimer's disease (AD) and other neurological disorders. The mechanisms that drive performance in this task are argued to rely on language and executive functions. However, there is little information regarding what specific aspects of these cognitive processes drive performance on this task. Objective:To understand which aspects of language (i.e., semantics, phonological output lexicon, phonological assembly) and executive function (i.e., mental set shifting; information updating and monitoring; inhibition of possible responses) are involved in the performance of animal fluency in people with AD. Methods:Animal fluency data from 58 people with probable AD from the DementiaBank Pittsburgh Corpus were analyzed. Number of clusters and switches were measured and nine word properties (e.g., frequency, familiarity) for each of the correct words (i.e., each word counting toward the total score, disregarding non-animals and repetitions) were determined. Random forests were used to understand which variables predicted the total number of correct words, and conditional inference trees were used to search for interactions between the variables. Finally, Wilcoxon tests were implemented to cross-validate the results, by comparing the performance of participants with scores below the norm in animal fluency against participants with scores within the norm based on a large normative sample. Results:Switches and age of acquisition emerged as the most important variables to predict total number of correct words in animal fluency in people with AD. Cross-validating the results, people with AD whose animal fluency scores fell below the norm produced fewer switches and words with lower age of acquisition than people with AD with scores in the normal range. Conclusion:The results indicate that people with AD rely on executive functioning (information updating and monitoring) and language (phonological output lexicon, not necessarily semantics) to produce words on animal fluency.
Project description:BACKGROUND:DNA methylation-based patterns of biological aging, known as epigenetic age acceleration, are predictive of all-cause mortality, but little is known about their association with cardiovascular disease (CVD). METHODS:We estimated 2 versions of epigenetic age acceleration (Horvath and Hannum) using whole-blood samples from 2543 blacks. Linear and Cox proportional hazards regression, respectively, were used to assess the association of age acceleration with carotid intima-media thickness (cross-sectionally) and incident cardiovascular events, including CVD mortality, myocardial infarction, fatal coronary heart disease, peripheral arterial disease, and heart failure, during a median 21-year follow-up. All models were adjusted for chronological age and traditional CVD risk factors. RESULTS:In comparison to chronological age, the 2 measures of epigenetic age acceleration were weaker, but independent, potential risk markers for subclinical atherosclerosis and most incident cardiovascular outcomes, including fatal coronary heart disease, peripheral arterial disease, and heart failure. For example, each 5-year increment of epigenetic age acceleration was associated with an average of 0.01 mm greater carotid intima-media thickness (each P≤0.01), and the hazard ratios (95% confidence intervals) of fatal coronary heart disease per 5-year increment in Horvath and Hannum age acceleration were 1.17 (1.02-1.33) and 1.22 (1.04-1.44), respectively. CONCLUSIONS:In this sample of blacks, increased epigenetic age acceleration in whole blood was a potential risk marker for incident fatal coronary heart disease, peripheral arterial disease, and heart failure independently of chronological age and traditional CVD risk factors. DNA methylation-based measures of biological aging may help to identify new pathophysiological mechanisms contributing to the development of CVD.
Project description:<h4>Background</h4>Accelerated epigenetic age has been proposed as a biomarker of increased aging, which may indicate disruptions in cellular and organ system homeostasis and thus contribute to sensitivity to environmental exposures.<h4>Methods</h4>Using 497 participants from the CATHGEN cohort, we evaluated whether accelerated epigenetic aging increases cardiovascular sensitivity to traffic-related air pollution (TRAP) exposure. We used residential proximity to major roadways and source apportioned air pollution models as measures of TRAP exposure, and chose peripheral arterial disease (PAD) and blood pressure as outcomes based on previous associations with TRAP. We used Horvath epigenetic age acceleration (AAD) and phenotypic age acceleration (PhenoAAD) as measures of age acceleration, and adjusted all models for chronological age, race, sex, smoking, and socioeconomic status.<h4>Results</h4>We observed significant interactions between TRAP and both AAD and PhenoAAD. Interactions indicated that increased epigenetic age acceleration elevated associations between proximity to roadways and PAD. Interactions were also observed between AAD and gasoline and diesel source apportioned PM<sub>2.5</sub>.<h4>Conclusion</h4>Epigenetic age acceleration may be a biomarker of sensitivity to air pollution, particularly for TRAP in urban cohorts. This presents a novel means by which to understand sensitivity to air pollution and provides a molecular measure of environmental sensitivity.
Project description:BACKGROUND:There is solid evidence that obesity induces the acceleration of liver epigenetic aging. However, unlike easily accessible blood or subcutaneous adipose tissue, little is known about the impact of obesity on epigenetic aging of metabolically active visceral adipose tissue (VAT). Herein, we aimed to test whether obesity accelerates VAT epigenetic aging in subjects with severe obesity. RESULTS:A significant and positive correlation between chronological age and epigenetic age, estimated with a reduced version of the Horvath's epigenetic clock, was found in both blood (r = 0.78, p = 9.4 × 10-12) and VAT (r = 0.80, p = 1.1 × 10-12). Epigenetic age acceleration, defined as the residual resulting from regressing epigenetic age on chronological age, was significantly correlated with body mass index (BMI) in VAT (r = 0.29, p = 0.037). Multivariate linear regression analysis showed that, after adjusting for chronological age, sex and metabolic syndrome status, BMI remained significantly associated with epigenetic age acceleration in VAT (beta = 0.15, p = 0.035), equivalent to 2.3?years for each 10 BMI units. Binomial logistic regression showed that BMI-adjusted epigenetic age acceleration in VAT was significantly associated with a higher loss of excess body weight following biliopancreatic diversion with duodenal switch surgery (odds ratio = 1.21; 95% CI = 1.04-1.48; p = 0.03). CONCLUSIONS:Epigenetic age acceleration increases with BMI in VAT, but not in blood, as previously reported in liver. These results suggest that obesity is associated with epigenetic age acceleration of metabolically active tissues. Further studies that deepen the physiological relevance of VAT epigenetic aging will help to better understand the onset of metabolic syndrome and weight loss dynamics following bariatric surgery.
Project description:<h4>Introduction</h4>The "epigenetic clock" is a DNA methylation-based estimate of biological age and is correlated with chronological age-the greatest risk factor for Alzheimer's disease (AD). Genetic and environmental risk factors exist for AD, several of which are potentially modifiable. In this study, we assess the relationship between the epigenetic clock and AD risk factors.<h4>Methods</h4>Multilevel models were used to assess the relationship between age acceleration (the residual of biological age regressed onto chronological age) and AD risk factors relating to cognitive reserve, lifestyle, disease, and genetics in the Generation Scotland study (n = 5100).<h4>Results</h4>We report significant associations between age acceleration and body mass index, total cholesterol to high-density lipoprotein cholesterol ratios, socioeconomic status, high blood pressure, and smoking behavior (Bonferroni-adjusted <i>P</i> < .05).<h4>Discussion</h4>Associations are present between environmental risk factors for AD and age acceleration. Measures to modify such risk factors might improve the risk profile for AD and the rate of biological ageing. Future longitudinal analyses are therefore warranted.
Project description:Markers of biological ageing have potential utility in primary care and public health. We developed a model of age based on untargeted metabolic profiling across multiple platforms, including nuclear magnetic resonance spectroscopy and liquid chromatography-mass spectrometry in urine and serum, within a large sample (N=2,239) from the UK Airwave cohort. We validated a subset of model predictors in a Finnish cohort including repeat measurements from 2,144 individuals. DNA methylation age was assessed for 1,110 participants using the Infinium HumanMethylation EPIC BeadChip. We investigated the determinants of accelerated ageing, including lifestyle and psychological risk factors for premature mortality. The metabolomic age model was well correlated with chronological age (mean r=0.86 across independent test sets). Increased metabolomic age acceleration (mAA) was associated after false discovery rate (FDR) correction with overweight/obesity, diabetes, heavy alcohol use and depression. DNA methylation age acceleration measures were uncorrelated with mAA. Increased DNA methylation phenotypic age acceleration (N = 1,110) was associated after FDR correction with heavy alcohol use, hypertension and low income. In conclusion, metabolomics is a promising approach for the assessment of biological age and appears complementary to established epigenetic clocks. Overall design: 1129 samples,including 14 replicates
Project description:Importance:Magnetic resonance imaging (MRI) studies of aging adults have shown substantial intersubject variability across various brain metrics, and some of this variability is likely attributable to chronological age being an imprecise measure of age-related change. Accurately quantifying one's biological age could allow better quantification of healthy and pathological changes in the aging brain. Objective:To investigate the association of DNA methylation (DNAm)-based biological age with cortical thickness and to assess whether biological age acceleration compared with chronological age captures unique variance in cortical thinning. Design, Setting, and Participants:This cross-sectional study used high-resolution structural brain MRI data collected from a sample of healthy aging adults who were participating in a larger ongoing neuroimaging study that began in May 2014. This population-based study accrued participants from the greater Omaha, Nebraska, metropolitan area. One hundred sixty healthy adults were contacted for the MRI component, 82 of whom participated in both DNAm and MRI study components. Data analysis was performed from March to June 2019. Main Outcomes and Measures:Vertexwise cortical thickness, DNAm-based biological age, and biological age acceleration compared with chronological age were measured. A pair of multivariable regression models were computed in which cortical thickness was regressed on DNAm-based biological age, controlling for sex in the first model and also controlling for chronological age in the second model. Results:Seventy-nine adult participants (38 women; mean [SD] age,?43.82 [14.50] years; age range, 22-72 years) were included in all final analyses. Advancing biological age was correlated with cortical thinning across frontal, superior temporal, inferior parietal, and medial occipital regions. In addition, biological age acceleration relative to chronological age was associated with cortical thinning in orbitofrontal, superior and inferior temporal, somatosensory, parahippocampal, and fusiform regions. Specifically, for every 1 year of biological age acceleration, cortical thickness would be expected to decrease by 0.024 mm (95% CI, -0.04 to -0.01 mm) in the left orbitofrontal cortex (partial r, -0.34; P?=?.002), 0.014 mm (95% CI, -0.02 to -0.01 mm) in the left superior temporal gyrus (partial r, -0.36; P?=?.001), 0.015 mm (95% CI, -0.02 to -0.01 mm) in the left fusiform gyrus (partial r, -0.38; P?=?.001), 0.015 mm (95% CI, -0.02 to -0.01 mm) in the right fusiform gyrus (partial r, -0.43; P?<?.001), 0.019 mm (95% CI, -0.03 to -0.01 mm) in the right inferior temporal sulcus (partial r, -0.34; P?=?.002), and 0.011 mm (95% CI, -0.02 to -0.01 mm) in the right primary somatosensory cortex (partial r, -0.37; P?=?.001). Conclusions and Relevance:To our knowledge, this is the first study to investigate vertexwise cortical thickness in relation to DNAm-based biological age, and the findings suggest that this metric of biological age may yield additional insight on healthy and pathological cortical aging compared with standard measures of chronological age alone.
Project description:Personality traits, such as Neuroticism and Conscientiousness, are associated with cognitive outcomes across the life span, including cognitive function in young adulthood and risk of cognitive impairment and dementia in old age. Research on personality and age-related cognition has focused primarily on memory-related tasks and outcomes. The purpose of this research is to address the relation between Five Factor Model personality traits and another critical marker of cognitive function that has received less attention-verbal fluency. We examine this relation across adulthood in 10 cohorts (11 samples) that totaled more than 90,000 participants (age range 16-101). Participants in all samples reported on their personality traits and completed at least one fluency task (semantic and/or letter). A meta-analysis of semantic fluency (N = 86,044) indicated that participants who scored lower in Neuroticism, and higher in Extraversion, Openness, and Conscientiousness, retrieved more words, independent of age, gender, and education. These associations generally replicated for the letter fluency task (3 samples; N = 11,551). Moderation analysis indicated that the associations between personality and semantic fluency were stronger in older samples (except for Openness) and among individuals with lower education. This pattern suggests that these associations are stronger in groups vulnerable to severe cognitive impairment. Personality traits have pervasive associations with fluency tasks that are replicable across samples and age groups. (PsycINFO Database Record (c) 2019 APA, all rights reserved).
Project description:Biomarkers of biological aging - DNA methylation age (DNAm age) and leukocyte telomere length (LTL)- correlate strongly with chronological age across the life course. It is, however, unclear how these measures of cellular wear and tear are associated with muscle strength and functional capacity, which are known to decline with older age and are associated with mortality. We investigated if DNAm age and LTL were associated with body composition and physical functioning by examining 48 monozygotic twin sisters.White blood cell DNAm age (predicted years) was calculated from Illumina 450 k BeadChip methylation data using an online calculator. DNAm age acceleration was defined from the residuals derived from a linear regression model of DNAm age on chronological age. LTL was measured by qPCR. Total body percentage of fat and lean mass were estimated using bioimpedance. Physical functioning was measured by grip strength, knee extension strength and by 10 m maximal walking speed test.In all participants, DNAm age (58.4?±?6.6) was lower than chronological age (61.3?±?5.9 years). Pairwise correlations of monozygotic co-twins were high for DNAm age (0.88, 95% CI 0.79, 0.97), age acceleration (0.68, 95% CI 0.30, 0.85) and LTL (0.77, 95% CI 0.60, 0.94). Increased age acceleration i.e. faster epigenetic aging compared to chronological age was associated with lower grip strength (??=?-?5.3 SE 1.9 p?=?0.011), but not with other measures of physical functioning or body composition. LTL was not associated with body composition or physical functioning.To conclude, accelerated DNAm age is associated with lower grip strength, a biomarker known to be associated with physiological aging, and which predicts decline in physical functioning and mortality. Further studies may clarify whether epigenetic aging explains the decline in muscle strength with aging or whether DNAm age just illustrates the progress of aging.