TY - JOUR T1 - A computational solution for bolstering reliability of epigenetic clocks: implications for clinical trials and longitudinal tracking JF - Nature Aging Y1 - 2022 A1 - Higgins-Chen, Albert T. A1 - Thrush, Kyra L. A1 - Wang, Yunzhang A1 - Minteer, Christopher J. A1 - Kuo, Pei-Lun A1 - Wang, Meng A1 - Niimi, Peter A1 - Sturm, Gabriel A1 - Lin, Jue A1 - Ann Zenobia Moore A1 - Bandinelli, Stefania A1 - Vinkers, Christiaan H. A1 - Vermetten, Eric A1 - Rutten, Bart P. F. A1 - Geuze, Elbert A1 - Okhuijsen-Pfeifer, Cynthia A1 - van der Horst, Marte A1 - Schreiter, Stefanie A1 - Gutwinski, Stefan A1 - Luykx, Jurjen J. A1 - Picard, Martin A1 - Ferrucci, Luigi A1 - Eileen M. Crimmins A1 - Boks, Marco P. A1 - Hägg, Sara A1 - Hu-Seliger, Tina T. A1 - Morgan E. Levine KW - Aging KW - Bioinformatics KW - computational models KW - DNA Methylation KW - predictive markers AB - Epigenetic clocks are widely used aging biomarkers calculated from DNA methylation data, but this data can be surprisingly unreliable. Here we show that technical noise produces deviations up to 9 years between replicates for six prominent epigenetic clocks, limiting their utility. We present a computational solution to bolster reliability, calculating principal components (PCs) from CpG-level data as input for biological age prediction. Our retrained PC versions of six clocks show agreement between most replicates within 1.5 years, improved detection of clock associations and intervention effects, and reliable longitudinal trajectories in vivo and in vitro. This method entails only one additional step compared to traditional clocks, requires no replicates or previous knowledge of CpG reliabilities for training, and can be applied to any existing or future epigenetic biomarker. The high reliability of PC-based clocks is critical for applications to personalized medicine, longitudinal tracking, in vitro studies and clinical trials of aging interventions. VL - 2 ER - TY - JOUR T1 - The Socioeconomic Gradient in Epigenetic Ageing Clocks: Evidence from the Multi-Ethnic Study of Atherosclerosis and the Health and Retirement Study. JF - Epigenetics Y1 - 2022 A1 - Lauren L Schmitz A1 - Zhao, Wei A1 - Scott M Ratliff A1 - Goodwin, Julia A1 - Miao, Jiacheng A1 - Lu, Qiongshi A1 - Guo, Xiuqing A1 - Kent D Taylor A1 - Ding, Jingzhong A1 - Liu, Yongmei A1 - Morgan E. Levine A1 - Smith, Jennifer A KW - DNA methylation age KW - epigenetic clock KW - polygenic score KW - socioeconomic status AB -

Epigenetic clocks have been widely used to predict disease risk in multiple tissues or cells. Their success as a measure of biological ageing has prompted research on the connection between epigenetic pathways of ageing and the socioeconomic gradient in health and mortality. However, studies examining social correlates of epigenetic ageing have yielded inconsistent results. We conducted a comprehensive, comparative analysis of associations between various dimensions of socioeconomic status (SES) (education, income, wealth, occupation, neighbourhood environment, and childhood SES) and eight epigenetic clocks in two well-powered US ageing studies: The Multi-Ethnic Study of Atherosclerosis (MESA) (n = 1,211) and the Health and Retirement Study (HRS) (n = 4,018). In both studies, we found robust associations between SES measures in adulthood and the GrimAge and DunedinPoAm clocks (Bonferroni-corrected -value < 0.01). In the HRS, significant associations with the Levine and Yang clocks were also evident. These associations were only partially mediated by smoking, alcohol consumption, and obesity, which suggests that differences in health behaviours alone cannot explain the SES gradient in epigenetic ageing in older adults. Further analyses revealed concurrent associations between polygenic risk for accelerated intrinsic epigenetic ageing, SES, and the Levine clock, indicating that genetic risk and social disadvantage may contribute additively to faster biological aging.

VL - 17 IS - 6 ER - TY - JOUR T1 - Associations of Age, Sex, Race/Ethnicity and Education with 13 Epigenetic Clocks in a Nationally Representative US Sample: The Health and Retirement Study. JF - The Journals of Gerontology: Series A Y1 - 2021 A1 - Eileen M. Crimmins A1 - Bharat Thyagarajan A1 - Morgan E. Levine A1 - David R Weir A1 - Jessica Faul KW - DNA Methylation KW - DunedinPoAm38 KW - Epigenetic Age KW - GrimAge KW - PhenoAgeAcceleration AB -

BACKGROUND: Many DNA methylation based indicators have been developed as summary measures of epigenetic aging. We examine the associations between 13 epigenetic clocks, including 4 second generation clocks, as well as the links of the clocks to social, demographic and behavioral factors known to be related to health outcomes: sex, race/ethnicity, socioeconomic status, obesity and lifetime smoking pack years.

METHODS: The Health and Retirement Study is the data source which is a nationally representative sample of Americans over age 50. Assessment of DNA methylation was based on the EPIC chip and epigenetic clocks were developed based on existing literature.

RESULTS: The clocks vary in the strength of their relationships with age, with each other and with independent variables. Second generation clocks trained on health related characteristics tend to relate more strongly to the sociodemographic and health behaviors known to be associated with health outcomes in this age group.

CONCLUSIONS: Users of this publicly available data set should be aware that epigenetic clocks vary in their relationships to age and to variables known to be related to the process of health change with age.

VL - 76 IS - 6 ER - TY - CHAP T1 - Trends in morbidity, healthy life expectancy, and the compression of morbidity T2 - Handbook of the Biology of Aging (Ninth Edition)Handbooks of Aging Y1 - 2021 A1 - Eileen M. Crimmins A1 - Yuan S Zhang A1 - Jung K Kim A1 - Morgan E. Levine ED - Musi, Nicolas ED - Hornsby, Peter J. KW - compression of morbidity KW - health trends KW - Healthy life expectancy KW - Morbidity AB - This chapter lays out the dimensions of morbidity and the processes linking morbidity and mortality. It provides evidence of recent trends in morbidity of the older American population: decline in some types of disability but not others, disease, and physiological dysregulation among the older American population. In addition, the chapter uses data from two recent cohorts to look at survival without disease and the age at onset of diseases. We have generally seen an increase in the prevalence and time with disease; but disease appears less disabling now than in the past. In addition, the onset of myocardial infarction appears to have been delayed by the recent control of biological risk. Most of the evidence does not support the idea that we have experienced a recent compression of morbidity; it does support some delay and retarding of progression of the morbidity process. JF - Handbook of the Biology of Aging (Ninth Edition)Handbooks of Aging PB - Academic Press SN - 978-0-12-815962-0 ER - TY - JOUR T1 - ASSOCIATIONS OF GENETICS AND LIFE COURSE CIRCUMSTANCES WITH A NOVEL AGING MEASURE THAT CAPTURES MORTALITY RISK JF - Innovation in Aging Y1 - 2019 A1 - Liu, Zuyun A1 - Chen, Xi A1 - Thomas M Gill A1 - Ma, Chao A1 - Eileen M. Crimmins A1 - Morgan E. Levine KW - Genetics KW - Mortality KW - mortality risk AB - We aimed to evaluate associations between a comprehensive set of factors, including genetics and childhood and adulthood circumstances, and a novel aging measure, Phenotypic Age (PhenoAge), which has been shown to capture mortality and morbidity risk in the U.S. population. Using data from 2339 adults (aged 51+) from the U.S. Health and Retirement Study, we found that together all 11 study domains (4 childhood and adulthood circumstances domains, 5 polygenic scores [PGSs] domains, and 1 demographics, and 1 behaviors domains) accounted for about 30\% of variance in PhenoAge after accounting for chronological age. Among the 4 circumstances domains, adulthood adversity was the largest contributor (9\%), while adulthood socioeconomic status (SES), childhood adversity, and childhood SES accounted for 2.8\%, 2.1\%, 0.7\%, respectively. All PGSs contributed 3.8\% of variance in PhenoAge (after accounting for chronological age). Further, using Hierarchical Clustering, we identified 6 distinct subpopulations/clusters based on the 4 circumstances domains, and 3 subpopulations/clusters of them that appear to represent disadvantaged circumstances were associated with higher PhenoAge. Finally, there was a significant gene-by-environment interaction between a previously validated PGS for coronary artery disease and the most apparently disadvantaged subpopulation/cluster, suggesting a multiplicative effect of adverse life course circumstances coupled with genetic risk on phenotypic aging. We concluded that socioenvironmental circumstances during childhood and adulthood account for a sizable proportion of differences in phenotypic aging among U.S. older adults. The disadvantaged subpopulations exhibited accelerated aging and the detrimental effects may be further exacerbated among persons with genetic predisposition to coronary artery disease. VL - 3 UR - https://doi.org/10.1093/geroni/igz038.1177 ER - TY - JOUR T1 - Associations of genetics, behaviors, and life course circumstances with a novel aging and healthspan measure: Evidence from the Health and Retirement Study. JF - PLoS Medicine Y1 - 2019 A1 - Liu, Zuyun A1 - Chen, Xi A1 - Thomas M Gill A1 - Ma, Chao A1 - Eileen M. Crimmins A1 - Morgan E. Levine KW - Genetics KW - Health Behavior KW - Life trajectories AB -

BACKGROUND: An individual's rate of aging directly influences his/her susceptibility to morbidity and mortality. Thus, quantifying aging and disentangling how various factors coalesce to produce between-person differences in the rate of aging, have important implications for potential interventions. We recently developed and validated a novel multi-system-based aging measure, Phenotypic Age (PhenoAge), which has been shown to capture mortality and morbidity risk in the full US population and diverse subpopulations. The aim of this study was to evaluate associations between PhenoAge and a comprehensive set of factors, including genetic scores, childhood and adulthood circumstances, and health behaviors, to determine the relative contributions of these factors to variance in this aging measure.

METHODS AND FINDINGS: Based on data from 2,339 adults (aged 51+ years, mean age 69.4 years, 56% female, and 93.9% non-Hispanic white) from the US Health and Retirement Study, we calculated PhenoAge and evaluated the multivariable associations for a comprehensive set of factors using 2 innovative approaches-Shapley value decomposition (the Shapley approach hereafter) and hierarchical clustering. The Shapley approach revealed that together all 11 study domains (4 childhood and adulthood circumstances domains, 5 polygenic score [PGS] domains, and 1 behavior domain, and 1 demographic domain) accounted for 29.2% (bootstrap standard error = 0.003) of variance in PhenoAge after adjustment for chronological age. Behaviors exhibited the greatest contribution to PhenoAge (9.2%), closely followed by adulthood adversity, which was suggested to contribute 9.0% of the variance in PhenoAge. Collectively, the PGSs contributed 3.8% of the variance in PhenoAge (after accounting for chronological age). Next, using hierarchical clustering, we identified 6 distinct subpopulations based on the 4 childhood and adulthood circumstances domains. Two of these subpopulations stood out as disadvantaged, exhibiting significantly higher PhenoAges on average. Finally, we observed a significant gene-by-environment interaction between a previously validated PGS for coronary artery disease and the seemingly most disadvantaged subpopulation, suggesting a multiplicative effect of adverse life course circumstances coupled with genetic risk on phenotypic aging. The main limitations of this study were the retrospective nature of self-reported circumstances, leading to possible recall biases, and the unrepresentative racial/ethnic makeup of the population.

CONCLUSIONS: In a sample of US older adults, genetic, behavioral, and socioenvironmental circumstances during childhood and adulthood account for about 30% of differences in phenotypic aging. Our results also suggest that the detrimental effects of disadvantaged life course circumstances for health and aging may be further exacerbated among persons with genetic predisposition to coronary artery disease. Finally, our finding that behaviors had the largest contribution to PhenoAge highlights a potential policy target. Nevertheless, further validation of these findings and identification of causal links are greatly needed.

VL - 16 IS - 6 U1 - http://www.ncbi.nlm.nih.gov/pubmed/31211779?dopt=Abstract ER - TY - JOUR T1 - Changing Disease Prevalence, Incidence, and Mortality Among Older Cohorts: The Health and Retirement Study JF - The Journals of Gerontology: Series A Y1 - 2019 A1 - Eileen M. Crimmins A1 - Yuan S Zhang A1 - Jung K Kim A1 - Morgan E. Levine KW - disease incidence KW - disease prevalence KW - Mortality AB - This article investigates changes in disease prevalence, incidence, and mortality among four cohorts of older persons in the Health and Retirement Study.We examine two cohorts initially aged 51 to 61, whom we call younger cohorts, and two older cohorts aged 70 to 80 at the start of observation. Each of the paired cohorts was born about 10 years apart. We follow the cohorts for approximately 10 years.The prevalence of cancer, stroke, and diabetes increased in later-born cohorts; while the prevalence of myocardial infarction decreased markedly in both later-born cohorts. The incidence of heart disease, myocardial infarction, and stroke decreased among those in the later-born older cohort; while only the incidence of myocardial infarction decreased in the later-born younger cohort. On the other hand, diabetes incidence increased among those in both later-born cohorts. Death rates among those with heart disease, cancer, and diabetes decreased in the later-born cohorts. The declining incidence of three cardiovascular conditions among those who are over age 70 reflects improving population health and has resulted in stemming the increase in prevalence of people with heart disease and stroke.While these results provide some important signs of improving population health, especially among those over 70; trends for those less than 70 in the United States are not as positive. VL - 74 UR - https://doi.org/10.1093/gerona/glz075 ER - TY - JOUR T1 - Education and Psychosocial Functioning Among Older Adults: 4-Year Change in Sense of Control and Hopelessness. JF - J Gerontol B Psychol Sci Soc Sci Y1 - 2018 A1 - Uchechi A Mitchell A1 - Jennifer A Ailshire A1 - Lauren L Brown A1 - Morgan E. Levine A1 - Eileen M. Crimmins KW - Activities of Daily Living KW - Aged KW - Educational Status KW - Female KW - Humans KW - Internal-External Control KW - Male KW - Middle Aged KW - Psychology KW - Sadness KW - Social participation KW - Social Support AB -

OBJECTIVES: This study investigates education differences in levels and change in sense of control and hopelessness among older adults.

METHOD: We used data from the Health and Retirement Study, an ongoing biennial survey of a nationally representative sample of older Americans, to examine education differences in sense of control (e.g., mastery and perceived constraints) and hopelessness. Our sample included 8,495 adults aged 52 and older who were interviewed in 2006/2008 and 2010/2012. We assessed separate models for change in sense of control and hopelessness, accounting for recent changes in social circumstances and health status.

RESULTS: Low mastery, perceived constraints, and hopelessness were highest among individuals with less than a high school education. Over a 4-year period, this group experienced the greatest declines in psychosocial functioning, as indicated by greater increases in low mastery, perceived constraints, and hopelessness. Education differences existed net of recent negative experiences, specifically the loss of intimate social relationships and social support and increases in disease and disability.

DISCUSSION: These findings highlight the importance of education for sense of control and hopelessness in older adulthood and demonstrate the cumulative advantage of higher levels of education for psychosocial functioning.

VL - 73 UR - http://psychsocgerontology.oxfordjournals.org/content/early/2016/03/23/geronb.gbw031.abstract IS - 5 U1 - http://www.ncbi.nlm.nih.gov/pubmed/27013537?dopt=Abstract U4 - Health and Retirement Study/Longitudinal analysis/Mastery/Perceived constraints ER - TY - JOUR T1 - Predictors and implications of accelerated cognitive aging JF - Biodemography and Social Biology Y1 - 2018 A1 - Morgan E. Levine A1 - Harrati, Amal A1 - Eileen M. Crimmins KW - BMI KW - Cognition & Reasoning KW - Risk Factors KW - Socioeconomic factors AB - Aging is a major risk factor for both normal and pathological cognitive decline. However, individuals vary in their rate of age-related decline. We developed an easily interpretable composite measure of cognitive age, and related both the level of cognitive age and cognitive slope to sociodemographic, genetic, and disease indicators and examined its prediction of dementia transition. Using a sample of 19,594 participants from the Health and Retirement Study, cognitive age was derived from a set of performance tests administered at each wave. Our findings reveal different conclusions as they relate to levels versus slopes of cognitive age, with more pronounced differences by sex and race/ethnicity for absolute levels of cognitive decline rather than for rates of declines. We also find that both level and slope of cognitive age are inversely related to education, as well as increased for persons with APOE ?4 and/or diabetes. Finally, results show that the slope in cognitive age predicts subsequent dementia among non-demented older adults. Overall, our study suggests that this measure is applicable to cross-sectional and longitudinal studies on cognitive aging, decline, and dementia with the goal of better understanding individual differences in cognitive decline. VL - 64 UR - https://www.tandfonline.com/doi/full/10.1080/19485565.2018.1552513https://www.tandfonline.com/doi/pdf/10.1080/19485565.2018.1552513 IS - 2 JO - Biodemography and Social Biology ER - TY - JOUR T1 - Contemporaneous Social Environment and the Architecture of Late-Life Gene Expression Profiles. JF - American Journal of Epidemiology Y1 - 2017 A1 - Morgan E. Levine A1 - Eileen M. Crimmins A1 - David R Weir A1 - Steven W. Cole KW - Genetics KW - Socioeconomic factors AB - Environmental or social challenges can stimulate a cascade of coordinated physiological changes in stress response systems. Unfortunately, chronic activation of these adaptations under conditions such as low socioeconomic status (SES) can have negative consequences for long-term health. While there is substantial evidence tying low SES to increased disease risk and reduced life expectancy, the underlying biology remains poorly understood. Using pilot data on 120 older adults from the Health and Retirement Study (United States, 2002-2010), we examined the associations between SES and gene expression levels in adulthood, with particular focus on a gene expression program known as the conserved transcriptional response to adversity. We also used a bioinformatics-based approach to assess the activity of specific gene regulation pathways involved in inflammation, antiviral responses, and stress-related neuroendocrine signaling. We found that low SES was related to increased expression of conserved transcriptional response to adversity genes and distinct patterns of proinflammatory, antiviral, and stress signaling (e.g., sympathetic nervous system and hypothalamic-pituitary-adrenal axis) transcription factor activation. VL - 186 IS - 5 U1 - http://www.ncbi.nlm.nih.gov/pubmed/28911009?dopt=Abstract ER - TY - JOUR T1 - Genetic architecture of epigenetic and neuronal ageing rates in human brain regions JF - Nature Communications Y1 - 2017 A1 - Lu, Ake T A1 - Hannon, Eilis A1 - Morgan E. Levine A1 - Eileen M. Crimmins A1 - Lunnon, Katie A1 - Mill, Jonathan A1 - Daniel H. Geschwind A1 - Horvath, Steve KW - Genetics AB - Identifying genes regulating the pace of epigenetic ageing represents a new frontier in genome-wide association studies (GWASs). Here using 1,796 brain samples from 1,163 individuals, we carry out a GWAS of two DNA methylation-based biomarkers of brain age: the epigenetic ageing rate and estimated proportion of neurons. Locus 17q11.2 is significantly associated (P=4.5 × 10 -9 ) with the ageing rate across five brain regions and harbours a cis-expression quantitative trait locus for EFCAB5 (P=3.4 × 10-20 ). Locus 1p36.12 is significantly associated (P=2.2 × 10-8 ) with epigenetic ageing of the prefrontal cortex, independent of the proportion of neurons. Our GWAS of the proportion of neurons identified two genome-wide significant loci (10q26 and 12p13.31) and resulted in a gene set that overlaps significantly with sets found by GWAS of age-related macular degeneration (P=1.4 × 10 -12 ), ulcerative colitis (P<1.0 × 10-20 ), type 2 diabetes (P=2.8 × 10-13 ), hip/waist circumference in men (P=1.1 × 10-9 ), schizophrenia (P=1.6 × 10-9 ), cognitive decline (P=5.3 × 10-4 ) and Parkinson's disease (P=8.6 × 10-3 ). VL - 8 UR - http://www.nature.com/doifinder/10.1038/ncomms15353http://www.nature.com/doifinder/10.1038/ncomms15353 JO - Nat Comms ER - TY - JOUR T1 - Effects of Recent Stress and Variation in the Serotonin Transporter Polymorphism (5-HTTLPR) on Depressive Symptoms: A Repeated-Measures Study of Adults Age 50 and Older. JF - Behavior Genetics Y1 - 2016 A1 - Thalida E. Arpawong A1 - Jinkook Lee A1 - Drystan F. Phillips A1 - Eileen M. Crimmins A1 - Morgan E. Levine A1 - Carol A Prescott KW - Aged KW - Alleles KW - depression KW - Depressive Disorder KW - Ethnic Groups KW - Female KW - Gene-Environment Interaction KW - Genetic Association Studies KW - Genetic Predisposition to Disease KW - Haplotypes KW - Humans KW - Life Change Events KW - Male KW - Middle Aged KW - Polymorphism, Single Nucleotide KW - Promoter Regions, Genetic KW - Serotonin Plasma Membrane Transport Proteins KW - Stress, Psychological AB -

Depending on genetic sensitivity to it, stress may affect depressive symptomatology differentially. Applying the stress-diathesis hypothesis to older adults, we postulate: (1) recent stress will associate with increased depressive symptom levels and (2) this effect will be greater for individuals with at least one short allele of the serotonin transporter gene promoter region (5-HTTLPR). Further, we employ a design that addresses specific limitations of many prior studies that have examined the 5-HTTLPR × SLE relation, by: (a) using a within-person repeated-measures design to address fluctuations that occur within individuals over time, increase power for detecting G × E, and address GE correlation; (b) studying reports of exogenous stressful events (those unlikely to be caused by depression) to help rule out reverse causation and negativity bias, and in order to assess stressors that are more etiologically relevant to depressive symptomatology in older adults. The sample is drawn from the Health and Retirement Study, a U.S. population-based study of older individuals (N = 28,248; mean age = 67.5; 57.3 % female; 80.7 % Non-Hispanic White, 14.9 % Hispanic/Latino, 4.5 % African American; genetic subsample = 12,332), from whom measures of depressive symptoms and exogenous stressors were collected biannually (1994-2010). Variation in the 5-HTTLPR was characterized via haplotype, using two single nucleotide polymorphisms (SNPs). Ordered logit models were constructed to predict levels of depressive symptoms from 5-HTTLPR and stressors, comparing results of the most commonly applied statistical approaches (i.e., comparing allelic and genotypic models, and continuous and categorical predictors) used in the literature. All models were stratified by race/ethnicity. Overall, results show a main effect of recent stress for all ethnic groups, and mixed results for the variation in 5-HTTLPR × stress interaction, contingent upon statistical model used. Findings suggest there may be a differential effect of stressors and 5-HTTLPR on depressive symptoms by ethnicity, but further research is needed, particularly when using a haplotype to characterize variation in 5-HTTLPR in population-based sample with a diverse ethnic composition.

PB - 46 VL - 46 IS - 1 U2 - PMC4720538 U4 - 5-HTTLPR/Depressive symptoms/G/Older adults/Race differences/Stressful life events/Genetic analysis ER - TY - JOUR T1 - A Genetic Network Associated With Stress Resistance, Longevity, and Cancer in Humans. JF - J Gerontol A Biol Sci Med Sci Y1 - 2016 A1 - Morgan E. Levine A1 - Eileen M. Crimmins KW - Aged KW - Aged, 80 and over KW - Aging KW - Alleles KW - Case-Control Studies KW - Gene Regulatory Networks KW - Genome-Wide Association Study KW - Genotype KW - Humans KW - Longevity KW - Longitudinal Studies KW - Middle Aged KW - Neoplasms KW - Phenotype KW - Polymorphism, Single Nucleotide KW - Smoking KW - Stress, Physiological KW - United States AB -

Human longevity and diseases are likely influenced by multiple interacting genes within a few biologically conserved pathways. Using long-lived smokers as a phenotype (n = 90)-a group whose survival may signify innate resilience-we conducted a genome-wide association study comparing them to smokers at ages 52-69 (n = 730). These results were used to conduct a functional interaction network and pathway analysis, to identify single nucleotide polymorphisms that collectively related to smokers' longevity. We identified a set of 215 single nucleotide polymorphisms (all of which had p <5×10(-3) in the genome-wide association study) that were located within genes making-up a functional interaction network. These single nucleotide polymorphisms were then used to create a weighted polygenic risk score that, using an independent validation sample of nonsmokers (N = 6,447), was found to be significantly associated with a 22% increase in the likelihood of being aged 90-99 (n = 253) and an over threefold increase in the likelihood of being a centenarian (n = 4), compared with being at ages 52-79 (n = 4,900). Additionally, the polygenic risk score was also associated with an 11% reduction in cancer prevalence over up to 18 years (odds ratio: 0.89, p = .011). Overall, using a unique phenotype and incorporating prior knowledge of biological networks, this study identified a set of single nucleotide polymorphisms that together appear to be important for human aging, stress resistance, cancer, and longevity.

VL - 71 IS - 6 U1 - http://www.ncbi.nlm.nih.gov/pubmed/26355015?dopt=Abstract ER - TY - JOUR T1 - Genetic variants near MLST8 and DHX57 affect the epigenetic age of the cerebellum. JF - Nat Commun Y1 - 2016 A1 - Lu, Ake T A1 - Hannon, Eilis A1 - Morgan E. Levine A1 - Hao, Ke A1 - Eileen M. Crimmins A1 - Lunnon, Katie A1 - Kozlenkov, Alexey A1 - Mill, Jonathan A1 - Dracheva, Stella A1 - Horvath, Steve KW - Adaptor Proteins, Signal Transducing KW - Aging KW - Cell Line KW - Cerebellum KW - Epigenesis, Genetic KW - Gene Expression Regulation KW - Genetic Variation KW - Genome-Wide Association Study KW - Humans KW - Linkage Disequilibrium KW - mTOR Associated Protein, LST8 Homolog AB -

DNA methylation (DNAm) levels lend themselves for defining an epigenetic biomarker of aging known as the 'epigenetic clock'. Our genome-wide association study (GWAS) of cerebellar epigenetic age acceleration identifies five significant (P<5.0 × 10(-8)) SNPs in two loci: 2p22.1 (inside gene DHX57) and 16p13.3 near gene MLST8 (a subunit of mTOR complex 1 and 2). We find that the SNP in 16p13.3 has a cis-acting effect on the expression levels of MLST8 (P=6.9 × 10(-18)) in most brain regions. In cerebellar samples, the SNP in 2p22.1 has a cis-effect on DHX57 (P=4.4 × 10(-5)). Gene sets found by our GWAS analysis of cerebellar age acceleration exhibit significant overlap with those of Alzheimer's disease (P=4.4 × 10(-15)), age-related macular degeneration (P=6.4 × 10(-6)), and Parkinson's disease (P=2.6 × 10(-4)). Overall, our results demonstrate the utility of a new paradigm for understanding aging and age-related diseases: it will be fruitful to use epigenetic tissue age as endophenotype in GWAS.

VL - 7 U1 - http://www.ncbi.nlm.nih.gov/pubmed/26830004?dopt=Abstract ER - TY - JOUR T1 - Childhood and later life stressors and increased inflammatory gene expression at older ages. JF - Soc Sci Med Y1 - 2015 A1 - Morgan E. Levine A1 - Steven W. Cole A1 - David R Weir A1 - Eileen M. Crimmins KW - Adolescent KW - Age Factors KW - Aged KW - Aged, 80 and over KW - Body Mass Index KW - Continental Population Groups KW - Cyclooxygenase 2 KW - Female KW - Health Status KW - Health Surveys KW - Humans KW - Interleukin-1beta KW - Interleukin-8 KW - Life Change Events KW - Male KW - Middle Aged KW - Obesity KW - RNA KW - Sex Factors KW - Smoking KW - Socioeconomic factors KW - Stress, Psychological AB -

Adverse experiences in early life have the ability to "get under the skin" and affect future health. This study examined the relative influence of adversities during childhood and adulthood in accounting for individual differences in pro-inflammatory gene expression in late life. Using a pilot-sample from the Health and Retirement Study (N = 114) aged from 51 to 95, OLS regression models were run to determine the association between a composite score from three proinflammatory gene expression levels (PTGS2, ILIB, and IL8) and 1) childhood trauma, 2) childhood SES, 3) childhood health, 4) adult traumas, and 5) low SES in adulthood. Our results showed that only childhood trauma was found to be associated with increased inflammatory transcription in late life. Furthermore, examination of interaction effects showed that childhood trauma exacerbated the influence of low SES in adulthood on elevated levels of inflammatory gene expression-signifying that having low SES in adulthood was most damaging for persons who had experienced traumatic events during their childhood. Overall our study suggests that traumas experienced during childhood may alter the stress response, leading to more sensitive reactivity throughout the lifespan. As a result, individuals who experienced greater adversity in early life may be at higher risk of late life health outcomes, particularly if adulthood adversity related to SES persists.

PB - 130 VL - 130 N1 - Times Cited: 0 0 U1 - http://www.ncbi.nlm.nih.gov/pubmed/25658624?dopt=Abstract U2 - PMC4394113 U4 - childhood health/adverse events/adverse events/trauma ER - TY - JOUR T1 - Loneliness, eudaimonia, and the human conserved transcriptional response to adversity. JF - Psychoneuroendocrinology Y1 - 2015 A1 - Steven W. Cole A1 - Morgan E. Levine A1 - Jesusa M. G. Arevalo A1 - Ma, Jeffrey A1 - David R Weir A1 - Eileen M. Crimmins KW - Aged KW - Aged, 80 and over KW - Down-Regulation KW - Female KW - Humans KW - Inflammation KW - Loneliness KW - Longitudinal Studies KW - Male KW - Mental Health KW - Middle Aged KW - social isolation KW - Social Support KW - Stress, Psychological KW - Transcriptome AB -

BACKGROUND: Chronic social adversity activates a conserved transcriptional response to adversity (CTRA) marked by increased expression of pro-inflammatory genes and decreased expression of antiviral- and antibody-related genes. Recent findings suggest that some psychological resilience factors may help buffer CTRA activation, but the relative impact of resilience and adversity factors remains poorly understood. Here we examined the relative strength of CTRA association for the two best-established psychological correlates of CTRA gene expression-the risk factor of perceived social isolation (loneliness) and the resilience factor of eudaimonic well-being (purpose and meaning in life).

METHODS: Peripheral blood samples and validated measures of loneliness and eudaimonic well-being were analyzed in 108 community-dwelling older adults participating in the longitudinal US Health and Retirement Study (56% female, mean age 73). Mixed effect linear model analyses quantified the strength of association between CTRA gene expression and measures of loneliness and eudaimonic well-being in separate and joint analyses.

RESULTS: As in previous studies, separate analyses found CTRA gene expression to be up-regulated in association with loneliness and down-regulated in association with eudaimonic well-being. In joint analyses, effects of loneliness were completely abrogated whereas eudaimonic well-being continued to associate with CTRA down-regulation. Similar eudaimonia-dominant effects were observed for positive and negative affect, optimism and pessimism, and anxiety symptoms. All results were independent of demographic and behavioral health risk factors.

CONCLUSIONS: Eudaimonic well-being may have the potential to compensate for the adverse impact of loneliness on CTRA gene expression. Findings suggest a novel approach to targeting the health risks associated with social isolation by promoting purpose and meaning in life.

PB - 62 VL - 62 UR - http://www.sciencedirect.com/science/article/pii/S0306453015002358 U1 - http://www.ncbi.nlm.nih.gov/pubmed/26246388?dopt=Abstract U2 - PMC4637182 U4 - Social genomics/Psychoneuroimmunology/Gene expression/Transcriptome/Microarray/Stress/Social support/Psychological well-being/Eudaimonia/Positive psychology ER - TY - JOUR T1 - A polygenic risk score associated with measures of depressive symptoms among older adults. JF - Biodemography Soc Biol Y1 - 2014 A1 - Morgan E. Levine A1 - Eileen M. Crimmins A1 - Carol A Prescott A1 - Drystan F. Phillips A1 - Thalida E. Arpawong A1 - Jinkook Lee KW - Aged KW - Aged, 80 and over KW - Depressive Disorder, Major KW - Female KW - Genetic Predisposition to Disease KW - Genetic Variation KW - Genome-Wide Association Study KW - Humans KW - Male KW - Middle Aged KW - Multifactorial Inheritance KW - Odds Ratio KW - Risk Factors AB -

It has been suggested that depression is a polygenic trait, arising from the influences of multiple loci with small individual effects. The aim of this study is to generate a polygenic risk score (PRS) to examine the association between genetic variation and depressive symptoms. Our analytic sample included N = 10,091 participants aged 50 and older from the Health and Retirement Study (HRS). Depressive symptoms were measured by Center for Epidemiological Studies-Depression scale (CESD) scores assessed on up to nine occasions across 18 years. We conducted a genome-wide association analysis for a discovery set (n = 7,000) and used the top 11 single-nucleotide polymorphisms, all with p < 10(-5) to generate a weighted PRS for our replication sample (n = 3,091). Results showed that the PRS was significantly associated with mean CESD score in the replication sample (β = .08, p = .002). The R(2) change for the inclusion of the PRS was .003. Using a multinomial logistic regression model, we also examined the association between genetic risk and chronicity of high (4+) CESD scores. We found that a one-standard-deviation increase in PRS was associated with a 36 percent increase in the odds of having chronically high CESD scores relative to never having had high CESD scores. Our findings are consistent with depression being a polygenic trait and suggest that the cumulative influence of multiple variants increases an individual's susceptibility for chronically experiencing high levels of depressive symptoms.

PB - 60 VL - 60 IS - 2 N1 - Times Cited: 0 SI 0 U1 - http://www.ncbi.nlm.nih.gov/pubmed/25343367?dopt=Abstract U2 - PMC4298361 U4 - GENOME-WIDE ASSOCIATION/INDIVIDUAL GENETIC RISK/MAJOR DEPRESSION/DISEASE RISK/HERITABILITY/genetics/genetics/depression/Depressive Symptoms/CES Depression Scale/CES Depression Scale/regression Analysis ER -