%0 Journal Article %J Nature Aging %D 2022 %T A computational solution for bolstering reliability of epigenetic clocks: implications for clinical trials and longitudinal tracking %A Higgins-Chen, Albert T. %A Thrush, Kyra L. %A Wang, Yunzhang %A Minteer, Christopher J. %A Kuo, Pei-Lun %A Wang, Meng %A Niimi, Peter %A Sturm, Gabriel %A Lin, Jue %A Ann Zenobia Moore %A Bandinelli, Stefania %A Vinkers, Christiaan H. %A Vermetten, Eric %A Rutten, Bart P. F. %A Geuze, Elbert %A Okhuijsen-Pfeifer, Cynthia %A van der Horst, Marte %A Schreiter, Stefanie %A Gutwinski, Stefan %A Luykx, Jurjen J. %A Picard, Martin %A Ferrucci, Luigi %A Eileen M. Crimmins %A Boks, Marco P. %A Hägg, Sara %A Hu-Seliger, Tina T. %A Morgan E. Levine %K Aging %K Bioinformatics %K computational models %K DNA Methylation %K predictive markers %X 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. %B Nature Aging %V 2 %P 644–661 %G eng %R 10.1038/s43587-022-00248-2 %0 Journal Article %J Research on Aging %D 2022 %T Do Early-Life Social, Behavioral, and Health Exposures Increase Later-Life Arthritis Incidence? %A Blakelee R Kemp %A Kenneth F Ferraro %A Patricia M Morton %A Thomas, Patricia A %A Sarah A Mustillo %A Eileen M. Crimmins %K Adverse Childhood Experiences %K Body Mass Index %K Cumulative inequality theory %K Osteoarthritis %K rheumatoid arthritis %X

OBJECTIVES: This study investigates direct and indirect influences of childhood social, behavioral, and health exposures on later-life osteoarthritis and rheumatoid arthritis development.

METHODS: Drawing from cumulative inequality theory and six waves of the Health and Retirement Study (2004-2014), we estimate structural equation modeling-based discrete-time survival analysis of the association between six childhood exposure domains and both osteoarthritis and rheumatoid arthritis incidence for men ( = 2720) and women ( = 2974). Using the delta method to test for mediation, we examine indirect effects via selected health-related risks and resources.

RESULTS: Risky adolescent behavior is associated with rheumatoid arthritis incidence for women (h.O.R. = 1.883, 95% C.I. [1.016, 3.490]), whereas several types of childhood exposures are associated with later-life osteoarthritis development for both men and women. Experiencing two or more childhood socioeconomic disadvantages is indirectly associated with osteoarthritis (men: coef. = 0.024, 95% C.I. [0.003, 0.045]; women: coef. = 0.111, 95% C.I. [0.071, 0.150]) and rheumatoid arthritis (men: coef. = 0.037, 95% C.I. [0.000, 0.074]; women: coef. = 0.097, 95% C.I. [0.035, 0.159]) development through adult body mass index.

DISCUSSION: Findings highlight the importance of childhood contexts in understanding the development of later-life osteoarthritis and rheumatoid arthritis.

%B Research on Aging %V 44 %P 479-493 %G eng %N 7-8 %R 10.1177/01640275211044979 %0 Journal Article %J Immunity & Ageing %D 2022 %T Evaluation of T-cell aging-related immune phenotypes in the context of biological aging and multimorbidity in the Health and Retirement Study. %A Ramasubramanian, Ramya %A Meier, Helen C S %A Vivek, Sithara %A Klopack, Eric %A Eileen M. Crimmins %A Jessica Faul %A Nikolich-Žugich, Janko %A Bharat Thyagarajan %K Adaptive immunity %K biological aging %K immune aging %K multimorbidity %X

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 (T) and increase in memory T-cells (T). 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: T/(T (Central Memory) + T (Effector Memory) + T (Effector)) (referred as T/T) 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 + T and CD8 + T/T 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 + T/T and CD4 + T had the strongest inverse association with biological age (β = -0.23; p = 0.003 and β = -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 + T/T and CD4 + T was inversely associated with multimorbidity. For CD4 + T/T, 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 + T subset were very similar to the associations seen with the CD4 + T/T. CD4 + T/T and CD4 + T 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 + T/T and CD4 + T 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.

%B Immunity & Ageing %V 19 %P 33 %G eng %N 1 %R 10.1186/s12979-022-00290-z %0 Journal Article %J American Journal of Clinical Pathology %D 2022 %T The role of cohabitation on adaptive and innate immune cell profiles in the Health and Retirement Study %A Ramasubramanian, Ramya %A Meier, Helen %A Eileen M. Crimmins %A Jessica Faul %A Bharat Thyagarajan %K adaptive immune cells %K Cohabitation %K Households %X Immune cells distribution is shaped by numerous factors including environmental factors, age, and genetics. Cohabitation has been associated with similar microbiomes, possibly due to dietary patterns and exposure to similar pathogens but has not been studied in the context of adaptive and innate immune systems previously. We used immunophenotyping data of 2283 households with participants living in the same household and compared it to 2283 randomly generated pairs of participants from the Health and Retirement study. The adaptive immune cells (subsets of T-cells and B-cells), and innate immune cells (monocytes, natural killer cells, and neutrophils) were compressed to two coordinates using multidimensional scaling. The Euclidean distances between participants in the same household were compared to the distances between the random pairs of participants using two sample independent t-tests. The mean distances of the immune coordinate points for adaptive immune cells between participants in the same household were lower than the randomly paired participants (p-value < 0.0001) and the variability of intra-household distances was lower than the random pairs (IQR: 7.18 vs 8.99). For the innate immune cells, the mean distances between participants in the same household were slightly lower than the randomly paired participants (p-value = 0.03) but the variability of the intra-household distances was higher than the random pairs (IQR: 4.08 vs 3.65). Variability in the adaptive immune system among participants living in the same household were substantially lower indicating the influence of shared environmental conditions in determining the adaptive immune profiles. %B American Journal of Clinical Pathology %V 158 %P S2 %G eng %R 10.1093/ajcp/aqac126.002 %0 Journal Article %J Innovation in Aging %D 2021 %T Association of GrimAge DNA methylation components and 2-year mortality in the Health and Retirement Study %A Meier, Helen %A Colter Mitchell %A Eileen M. Crimmins %A Bharat Thyagarajan %A Jessica Faul %K 2-year mortality %K DNA Methylation %K GrimAge %X DNA methylation (DNAm) patterns related to age and aging phenotypes (i.e., epigenetic clocks) are of growing interest as indicators of biological age and risk of negative health outcomes. We investigated associations between the components of GrimAge, an epigenetic clock estimated from DNAm patterns for seven blood protein levels and smoking pack years, and 2-year mortality in the Health and Retirement Study (HRS) to determine if any of the DNAm subcomponents were driving observed associations. A representative subsample of individuals who participated in the HRS 2016 Venus Blood Study were included in this analysis (N=3430). DNAm was measured with the Infinium Methylation EPIC BeadChip. Deaths that occurred between 2016 and 2018 contributed to 2-year mortality estimates (N=159, 4.5% of the sample). Weighted logistic regression estimated the association first between GrimAge and 2-year mortality and second between the DNAm subcomponents and 2-year mortality. All models were adjusted for age, sex, race/ethnicity, education, current smoking status, smoking pack years and cell composition of the biological sample. The average GrimAge for participants with and without 2-year mortality was 77 years 68 years respectively. A one-year increase in GrimAge was associated with 17% higher odds of 2-year mortality (95% CI: 1.16, 1.17). Two of the seven DNAm blood protein subcomponents of GrimAge (TIMP metallopeptidase inhibitor 1, adrenomedullin) and DNAm smoking pack years were associated with 2-year mortality and DNAm smoking pack years appeared to drive the overall GrimAge association with 2-year mortality. GrimAge was a better predictor of 2-year mortality than the DNAm subcomponents individually. %B Innovation in Aging %V 5 %P 675 %G eng %N Suppl _1 %R https://doi.org/10.1093/geroni/igab046.2525 %0 Journal Article %J Innovation in Aging %D 2021 %T Epigenome Wide Associations of Smoking Behavior in the Health and Retirement Study %A Fisher, Jonah %A Meier, Helen %A Jessica Faul %A Colter Mitchell %A Eileen M. Crimmins %A Bharat Thyagarajan %K DNA Methylation %K epigenome-wide association studies %K Smoking %X DNA methylation (DNAm) is an increasingly popular biomarker of health and aging outcomes. Smoking behaviors have a significant and well documented correlation with methylation signatures within the epigenome and are important confounding variables to account for in epigenome-wide association studies (EWAS). However, the common classification of individuals as ‘current’, ‘former’, and ‘never’ smokers may miss crucial DNAm patterns associated with other smoking behaviors such as duration, intensity, and frequency of cigarette smoking, resulting in an underestimation of the contribution of smoking behaviors to DNAm and potentially biasing EWAS results. We investigated associations between multiple smoking behavioral phenotypes (smoking pack years, smoking duration, smoking start age, and smoking end age) and single site DNAm using linear regressions adjusting for age, sex, race/ethnicity, education, and cell-type proportions in a subsample of individuals who participated in the HRS 2016 Venous Blood Study (N=1,775). DNAm was measured using the Infinium Methylation EPIC BeadChip. All 4 phenotypes had significant associations (FDR < 0.05) with many methylation sites (packyears=6859, smoking duration=6572, start age=11374, quit age=773). There was not much overlap in DNAm sites between the full set of models with only 6 overlapping between all 4. However, the phenotypes packyears and smoking duration showed large overlap (N=3782). Results suggest additional smoking phenotypes beyond current/former/never smoker classification should be included in EWAS analyses to appropriately account for the influence of smoking behaviors on DNAm. %B Innovation in Aging %V 5 %P 668 %G eng %N Suppl _1 %R https://doi.org/10.1093/geroni/igab046.2503 %0 Journal Article %J Housing Studies %D 2021 %T Housing and cardiometabolic risk among older renters and homeowners %A Mawhorter, Sarah %A Eileen M. Crimmins %A Jennifer A Ailshire %K cardiometabolic risk %K health %K Homeownership %K housing affordability %K housing conditions %X Scholars consistently find that renters have poorer health outcomes when compared with homeowners. Health disparities between renters and homeowners likely widen over the life course, yet few studies have examined this link among older adults, and the connection is not fully understood. Homeowners’ relative socio-economic advantage may explain their better health; renters also more commonly experience adverse housing conditions and financial challenges, both of which can harm health. In this paper, we analyse the extent to which socio-economic advantage, housing conditions, and financial strain explain the relationship between homeownership and health among adults over age 50, using Health and Retirement Study 2010/2012 data to assess cardiometabolic risk (CMR) levels using biomarkers for inflammation, cardiovascular health, and metabolic function. We find that people living with poor housing conditions and financial strain have higher CMR levels, even taking socio-economic advantage into account. This analysis sheds light on the housing-related health challenges of older adults, especially older renters. %B Housing Studies %@ 0267-3037 %G eng %R 10.1080/02673037.2021.1941792 %0 Book Section %B Handbook of the Biology of Aging (Ninth Edition)Handbooks of Aging %D 2021 %T Trends in morbidity, healthy life expectancy, and the compression of morbidity %A Eileen M. Crimmins %A Yuan S Zhang %A Jung K Kim %A Morgan E. Levine %E Musi, Nicolas %E Hornsby, Peter J. %K compression of morbidity %K health trends %K Healthy life expectancy %K Morbidity %X 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. %B Handbook of the Biology of Aging (Ninth Edition)Handbooks of Aging %I Academic Press %P 405-414 %@ 978-0-12-815962-0 %G eng %& 19 %R https://doi.org/10.1016/B978-0-12-815962-0.00019-6 %0 Journal Article %J Innovation in Aging %D 2019 %T ASSOCIATIONS OF GENETICS AND LIFE COURSE CIRCUMSTANCES WITH A NOVEL AGING MEASURE THAT CAPTURES MORTALITY RISK %A Liu, Zuyun %A Chen, Xi %A Thomas M Gill %A Ma, Chao %A Eileen M. Crimmins %A Morgan E. Levine %K Genetics %K Mortality %K mortality risk %X 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. %B Innovation in Aging %V 3 %P S322-S323 %8 11 %G eng %U https://doi.org/10.1093/geroni/igz038.1177 %R 10.1093/geroni/igz038.1177 %0 Journal Article %J PLoS Medicine %D 2019 %T Associations of genetics, behaviors, and life course circumstances with a novel aging and healthspan measure: Evidence from the Health and Retirement Study. %A Liu, Zuyun %A Chen, Xi %A Thomas M Gill %A Ma, Chao %A Eileen M. Crimmins %A Morgan E. Levine %K Genetics %K Health Behavior %K Life trajectories %X

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.

%B PLoS Medicine %V 16 %P e1002827 %G eng %N 6 %1 http://www.ncbi.nlm.nih.gov/pubmed/31211779?dopt=Abstract %R 10.1371/journal.pmed.1002827 %0 Journal Article %J The Journals of Gerontology: Series A %D 2019 %T Change in cardiometabolic risk among blacks, whites and Hispanics: findings from the Health and Retirement Study %A Uchechi A Mitchell %A Jennifer A Ailshire %A Eileen M. Crimmins %K Biomarkers %K C-reactive protein %K Cardiovascular health %K Racial/ethnic differences %K Risk Factors %X Background Blacks experience greater multi-system physiological dysregulation, or cumulative biological risk, which is associated with poor cardiometabolic health and mortality. In this study, we assess race differences in change in risk over four years among older whites, blacks and Hispanics. Method We examined race differences in 4-year change in individual biomarkers and a cumulative measure of risk—cardiometabolic risk (CMR)—using data for each respondent from two waves of the Health and Retirement Study’s biomarker assessment (n=5,512). CMR is a count of high-risk cardiovascular and metabolic biomarkers. We estimated mean CMR at baseline and follow-up by race/ethnicity, and used logistic regression to determine whether race differences exist in 4-year transitions between high- and low-risk states for individual biomarkers. Results Blacks had higher baseline CMR than whites and Hispanics and experienced an increase in risk over four years; conversely, CMR decreased among whites and Hispanics. Blacks were more likely to develop high-risk pulse pressure and high-risk hemoglobin A1c, which contributed to increases in CMR. Whites and Hispanics were more likely to become low-risk on C-reactive protein and HDL cholesterol which contributed to declines in CMR. Race differences in transitions between risk states remained after controlling for social, behavioral and health care related factors. However, the racial patterning of these differences was influenced by disease diagnosis and medication use. Conclusions We show that the cardiometabolic health of older blacks worsens as they age both absolutely and relative to that of whites and Hispanics because of poor blood pressure control and diabetes prevention. %B The Journals of Gerontology: Series A %V 74 %P 240-246 %G eng %U https://academic.oup.com/biomedgerontology/advance-article/doi/10.1093/gerona/gly026/4857183http://academic.oup.com/biomedgerontology/advance-article-pdf/doi/10.1093/gerona/gly026/23921802/gly026.pdf %N 2 %R 10.1093/gerona/gly026 %0 Journal Article %J J Gerontol B Psychol Sci Soc Sci %D 2018 %T Education and Psychosocial Functioning Among Older Adults: 4-Year Change in Sense of Control and Hopelessness. %A Uchechi A Mitchell %A Jennifer A Ailshire %A Lauren L Brown %A Morgan E. Levine %A Eileen M. Crimmins %K Activities of Daily Living %K Aged %K Educational Status %K Female %K Humans %K Internal-External Control %K Male %K Middle Aged %K Psychology %K Sadness %K Social participation %K Social Support %X

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.

%B J Gerontol B Psychol Sci Soc Sci %V 73 %P 849-859 %8 2018 Jun 14 %G eng %U http://psychsocgerontology.oxfordjournals.org/content/early/2016/03/23/geronb.gbw031.abstract %N 5 %1 http://www.ncbi.nlm.nih.gov/pubmed/27013537?dopt=Abstract %4 Health and Retirement Study/Longitudinal analysis/Mastery/Perceived constraints %$ 999999 %R 10.1093/geronb/gbw031 %0 Journal Article %J Journal of Immunological Methods %D 2018 %T Effect of delayed cell processing and cryopreservation on immunophenotyping in multicenter population studies. %A Bharat Thyagarajan %A Barcelo, Helene %A Eileen M. Crimmins %A David R Weir %A Minnerath, Sharon %A Vivek, Sithara %A Jessica Faul %K Cell Separation %K Cryopreservation %K Immunophenotyping %K Leukocytes %K Time Factors %X

Variability induced by delayed cell processing and cell cryopreservation presents unique challenges for immunophenotyping in large population studies. We conducted a pilot study to evaluate the effect of delayed cell processing and cryopreservation on cell percentages obtained by immunophenotyping. We collected blood from 20 volunteers and compared the effect of (a) delayed cell processing up to 72 h (b) cryopreservation and (c) the combined effect of delayed cell processing and cryopreservation on immunophenotyping of 31 cell subsets that included several subsets of T, B, Natural Killer (NK) cells, monocytes and dendritic cells using both whole blood collected in EDTA tubes and peripheral blood mononuclear cells collected in CPT tubes. We found the delayed cell processing up to 72 h or cryopreservation alone did not significantly affect the percentages T cells, dendritic cells or monocytes but significantly increased the percentage of B cells and NK cells (p for trend ≤0.01) but. However combination of delayed cell processing up to 72 h and cryopreservation significantly increased the percentage of T cells as compared to cells processed immediately (p for trend <0.0001) while a delayed cell processing followed by cryopreservation decreased the percentage of NK cells (p for trend <0.0001). Total B-cells increased significantly with a 24-48 h delay in cell processing and cryopreservation but not at 72 h. The percentages of monocytes and dendritic cells remained unaffected by the combination of delayed cell processing and cryopreservation. These findings suggest that immunophenotyping of several immune cell subsets can be successfully implemented in large population studies as long as blood is processed within 48 h of biospecimen collection though some cell subsets may be more susceptible to a combination of delayed cell processing and cryopreservation.

%B Journal of Immunological Methods %V 463 %P 61-70 %G eng %R 10.1016/j.jim.2018.09.007 %0 Book Section %B Oxford Textbook of Geriatric Medicine %D 2017 %T Ageing in North America: Canada and the United States %A Eileen M. Crimmins %A Hiram Beltrán-Sánchez %A Lauren L Brown %A Yon, Yongjie %A Michel, Jean-Pierre %A Beattie, B. Lynn %A Martin, Finbarr C. %A Jeremy D Walston %K Aging %K Cross-National %B Oxford Textbook of Geriatric Medicine %7 3rd %I Oxford University Press %C Cary, NC %P 19-26 %@ 978-0198701590 %G eng %& 3 %0 Journal Article %J The Journals of Gerontology Series A: Biological Sciences and Medical Sciences %D 2017 %T Clinical Trials Targeting Aging and Age-Related Multimorbidity %A Mark A. Espeland %A Eileen M. Crimmins %A Brandon R. Grossardt %A Jill P. Crandall %A Jonathan A. L. Gelfond %A Tamara B Harris %A Stephen B Kritchevsky %A JoAnn E Manson %A Jennifer G Robinson %A Walter A Rocca %A Temprosa, Marinella %A Thomas, Fridtjof %A Robert B Wallace %A Barzilai, Nir %K Chronic disease %K Clinical trials %K Older Adults %X Background: There is growing interest in identifying interventions that may increase health span by targeting biological processes underlying aging. The design of efficient and rigorous clinical trials to assess these interventions requires careful consideration of eligibility criteria, outcomes, sample size, and monitoring plans. Methods: Experienced geriatrics researchers and clinical trialists collaborated to provide advice on clinical trial design. Results: Outcomes based on the accumulation and incidence of age-related chronic diseases are attractive for clinical trials targeting aging. Accumulation and incidence rates of multimorbidity outcomes were developed by selecting at-risk subsets of individuals from three large cohort studies of older individuals. These provide representative benchmark data for decisions on eligibility, duration, and assessment protocols. Monitoring rules should be sensitive to targeting aging-related, rather than disease-specific, outcomes. Conclusions: Clinical trials targeting aging are feasible, but require careful design consideration and monitoring rules. %B The Journals of Gerontology Series A: Biological Sciences and Medical Sciences %V 72 %P 355-361 %G eng %U https://academic.oup.com/biomedgerontology/article-lookup/doi/10.1093/gerona/glw220https://academic.oup.com/biomedgerontology/article/2328606/Clinical-Trials-Targeting-Aging-and-AgeRelated %N 3 %! GERONA %R 10.1093/gerona/glw220 %0 Journal Article %J Nature Communications %D 2017 %T Genetic architecture of epigenetic and neuronal ageing rates in human brain regions %A Lu, Ake T %A Hannon, Eilis %A Morgan E. Levine %A Eileen M. Crimmins %A Lunnon, Katie %A Mill, Jonathan %A Daniel H. Geschwind %A Horvath, Steve %K Genetics %X 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 ). %B Nature Communications %V 8 %8 Jun-05-2018 %G eng %U http://www.nature.com/doifinder/10.1038/ncomms15353http://www.nature.com/doifinder/10.1038/ncomms15353 %! Nat Comms %R 10.1038/ncomms15353 %0 Journal Article %J Labour Economics %D 2016 %T The effect of job loss on health: Evidence from biomarkers %A Pierre-Carl Michaud %A Eileen M. Crimmins %A Michael D Hurd %K Biomarkers %K Health Shocks %K Job loss %K Older Adults %K Retirement Planning and Satisfaction %X We estimate the effect of job loss on objective measures of physiological dysregulation using biomarker measures collected by the Health and Retirement Study in 2006 and 2008 and longitudinal self-reports of work status. We distinguish between group or individual layoffs, and business closures. Workers who are laid off from their job have lower health as measured by biomarker, whereas workers laid off in the context of a business closure do not. Estimates matching respondents wave-by-wave on self-reported health conditions and subjective job loss expectations prior to job loss, suggest strong effects of layoffs on biomarkers, in particular for glycosylated hemoglobin (HbA1c). A layoff could increase annual mortality rates by 10.3%, consistent with other evidence of the effect of group layoffs on mortality. %B Labour Economics %V 41 %P 194 - 203 %8 Jan-08-2016 %G eng %U http://linkinghub.elsevier.com/retrieve/pii/S0927537116300288http://api.elsevier.com/content/article/PII:S0927537116300288?httpAccept=text/xmlhttp://api.elsevier.com/content/article/PII:S0927537116300288?httpAccept=text/plain %! Labour Economics %R 10.1016/j.labeco.2016.05.014 %0 Journal Article %J Nat Commun %D 2016 %T Genetic variants near MLST8 and DHX57 affect the epigenetic age of the cerebellum. %A Lu, Ake T %A Hannon, Eilis %A Morgan E. Levine %A Hao, Ke %A Eileen M. Crimmins %A Lunnon, Katie %A Kozlenkov, Alexey %A Mill, Jonathan %A Dracheva, Stella %A Horvath, Steve %K Adaptor Proteins, Signal Transducing %K Aging %K Cell Line %K Cerebellum %K Epigenesis, Genetic %K Gene Expression Regulation %K Genetic Variation %K Genome-Wide Association Study %K Humans %K Linkage Disequilibrium %K mTOR Associated Protein, LST8 Homolog %X

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.

%B Nat Commun %V 7 %P 10561 %8 2016 Feb 02 %G eng %1 http://www.ncbi.nlm.nih.gov/pubmed/26830004?dopt=Abstract %R 10.1038/ncomms10561 %0 Journal Article %J Demography %D 2015 %T Disease incidence and mortality among older Americans and Europeans. %A Sole-Auro, Aida %A Pierre-Carl Michaud %A Michael D Hurd %A Eileen M. Crimmins %K Age Distribution %K Aged %K Chronic disease %K Europe %K Health Behavior %K Humans %K Incidence %K Middle Aged %K Neoplasms %K Prevalence %K Risk Factors %K Sex Distribution %K Socioeconomic factors %K United States %X

Recent research has shown a widening gap in life expectancy at age 50 between the United States and Europe as well as large differences in the prevalence of diseases at older ages. Little is known about the processes determining international differences in the prevalence of chronic diseases. Higher prevalence of disease could result from either higher incidence or longer disease-specific survival. This article uses comparable longitudinal data from 2004 and 2006 for populations aged 50 to 79 from the United States and from a selected group of European countries to examine age-specific differences in prevalence and incidence of heart disease, stroke, lung disease, diabetes, hypertension, and cancer as well as mortality associated with each disease. Not surprisingly, we find that Americans have higher disease prevalence. For heart disease, diabetes, and cancer, incidence is lower in Europe when we control for sociodemographic and health behavior differences in risk, and these differences explain much of the prevalence gap at older ages. On the other hand, incidence is higher in Europe for lung disease and not different between Europe and the United States for hypertension and stroke. Our findings do not suggest a survival advantage conditional on disease in Europe compared with the United States. Therefore, the origin of the higher disease prevalence at older ages in the United States is to be found in higher prevalence earlier in the life course and, for some conditions, higher incidence between ages 50 and 79.

%B Demography %V 52 %P 593-611 %8 2015 Apr %G eng %N 2 %1 http://www.ncbi.nlm.nih.gov/pubmed/25715676?dopt=Abstract %R 10.1007/s13524-015-0372-7 %0 Journal Article %J Psychoneuroendocrinology %D 2015 %T Loneliness, eudaimonia, and the human conserved transcriptional response to adversity. %A Steven W. Cole %A Morgan E. Levine %A Jesusa M. G. Arevalo %A Ma, Jeffrey %A David R Weir %A Eileen M. Crimmins %K Aged %K Aged, 80 and over %K Down-Regulation %K Female %K Humans %K Inflammation %K Loneliness %K Longitudinal Studies %K Male %K Mental Health %K Middle Aged %K social isolation %K Social Support %K Stress, Psychological %K Transcriptome %X

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.

%B Psychoneuroendocrinology %I 62 %V 62 %P 11-7 %8 2015 Dec %G eng %U http://www.sciencedirect.com/science/article/pii/S0306453015002358 %1 http://www.ncbi.nlm.nih.gov/pubmed/26246388?dopt=Abstract %2 PMC4637182 %4 Social genomics/Psychoneuroimmunology/Gene expression/Transcriptome/Microarray/Stress/Social support/Psychological well-being/Eudaimonia/Positive psychology %$ 999999 %R 10.1016/j.psyneuen.2015.07.001 %0 Report %D 2014 %T The Effect of Job Loss on Health: Evidence from Biomarkers %A Pierre-Carl Michaud %A Eileen M. Crimmins %A Michael D Hurd %K Demographics %K Employment and Labor Force %K Health Conditions and Status %K Methodology %X The effect of job loss on health may play an important role in the development of the SES-health gradient. In this paper, we estimate the effect of job loss on objective measures of physiological dysregulation using longitudinal data from the Health and Retirement Study and biomarker measures collected in 2006 and 2008. We use a variety of econometric methods to account for selection and reverse causality.Distinguishing between layoffs and business closures, we find no evidence that business closures lead to worse health outcomes. We also find no evidence that biomarker health measures predict subsequent job loss because of business closures. We do find evidence that layoffs lead to diminished health. Although this finding appears to be robust to confounders, we find that reverse causality tends to bias downward our estimates. Matching estimates, which account for self-reported health conditions prior to the layoff and subjective job loss expectations, suggest even stronger estimates of the effect of layoffs on health as measured from biomarkers, in particular for glycosylated hemoglobin (HbA1c) and C-reactive protein (CRP). Overall, we estimate that a layoff could increase annual mortality rates by 9.4 , which is consistent with other evidence of the effect of mass layoffs on mortality. %I Bonn, Germany, Institute for the Study of Labor %G eng %4 job loss/health/SES-health gradient/biomarkers/Socioeconomic Status/Self assessed health/Layoffs/biomarkers %$ 999999 %0 Journal Article %J Biodemography Soc Biol %D 2014 %T Validation of blood-based assays using dried blood spots for use in large population studies. %A Eileen M. Crimmins %A Jung K Kim %A Heather McCreath %A Jessica Faul %A David R Weir %A Teresa Seeman %K Biomarkers %K C-reactive protein %K Cholesterol %K Cholesterol, HDL %K Cystatin C %K Dried Blood Spot Testing %K Glycated Hemoglobin A %K Humans %K Middle Aged %K Reference Values %K Reproducibility of Results %X

Assessment of health in large population studies has increasingly incorporated measures of blood-based biomarkers based on the use of dried blood spots (DBS). The validity of DBS assessments made by labs used by large studies is addressed by comparing assay values from DBS collected using conditions similar to those used in the field with values from whole blood samples. The DBS approach generates values that are strongly related to whole blood levels of HbA1c, cystatin C, and C-reactive protein. Assessing lipid levels reliably with DBS appears to be a greater challenge. However, even when DBS values and values from venous blood are highly correlated, they are often on a different scale, and using conventional cutoffs may be misleading.

%B Biodemography Soc Biol %V 60 %P 38-48 %8 2014 %G eng %U http://www.tandfonline.com/doi/abs/10.1080/19485565.2014.901885 %N 1 %1 http://www.ncbi.nlm.nih.gov/pubmed/24784986?dopt=Abstract %! Biodemography and Social Biology %R 10.1080/19485565.2014.901885 %0 Journal Article %J Demography %D 2013 %T Trends in late-life activity limitations in the United States: an update from five national surveys. %A Vicki A Freedman %A Brenda C Spillman %A Patricia Andreski %A Jennifer C. Cornman %A Eileen M. Crimmins %A Kramarow, Ellen %A Lubitz, James %A Linda G Martin %A Sharon S. Merkin %A Robert F. Schoeni %A Teresa Seeman %A Timothy A Waidmann %K Activities of Daily Living %K Aged %K Aged, 80 and over %K Disabled Persons %K Female %K Health Surveys %K Humans %K Male %K Mobility Limitation %K Models, Statistical %K United States %X

This article updates trends from five national U.S. surveys to determine whether the prevalence of activity limitations among the older population continued to decline in the first decade of the twenty-first century. Findings across studies suggest that personal care and domestic activity limitations may have continued to decline for those ages 85 and older from 2000 to 2008, but generally were flat since 2000 for those ages 65-84. Modest increases were observed for the 55- to 64-year-old group approaching late life, although prevalence remained low for this age group. Inclusion of the institutional population is important for assessing trends among those ages 85 and older in particular.

%B Demography %I 50 %V 50 %P 661-71 %8 2013 Apr %G eng %N 2 %1 http://www.ncbi.nlm.nih.gov/pubmed/23104207?dopt=Abstract %2 PMC3586750 %4 methodology/Meta-analysis/ADL and IADL Impairments/Public Policy/health Care Costs/PREVALENCE %$ 68982 %R 10.1007/s13524-012-0167-z %0 Report %D 2011 %T Results from the Health and Retirement Study Biomarker Validation Project %A Eileen M. Crimmins %A Jung K Kim %A Heather McCreath %A Teresa Seeman %K Health Conditions and Status %K Methodology %I Ann Arbor, The University of Michigan %G eng %4 Survey Methods/Biomarker data %$ 62870 %0 Journal Article %J Demography %D 2004 %T Resolving inconsistencies in trends in old-age disability: report from a technical working group. %A Vicki A Freedman %A Eileen M. Crimmins %A Robert F. Schoeni %A Brenda C Spillman %A Aykan, Hakan %A Kramarow, Ellen %A Land, Kenneth %A Lubitz, James %A Kenneth G. Manton %A Linda G Martin %A Shinberg, Diane %A Timothy A Waidmann %K Activities of Daily Living %K Age Factors %K Aged %K Aged, 80 and over %K Chronic disease %K Disabled Persons %K Female %K Health Surveys %K Homemaker Services %K Humans %K Male %K Models, Statistical %K Self-Help Devices %K United States %X

In September 2002, a technical working group met to resolve previously published inconsistencies across national surveys in trends in activity limitations among the older population. The 12-person panel prepared estimates from five national data sets and investigated methodological sources of the inconsistencies among the population aged 70 and older from the early 1980s to 2001. Although the evidence was mixed for the 1980s and it is difficult to pinpoint when in the 1990s the decline began, during the mid- and late 1990s, the panel found consistent declines on the order of 1%-2.5% per year for two commonly used measures in the disability literature: difficulty with daily activities and help with daily activities. Mixed evidence was found for a third measure: the use of help or equipment with daily activities. The panel also found agreement across surveys that the proportion of older persons who receive help with bathing has declined at the same time as the proportion who use only equipment (but not personal care) to bathe has increased. In comparing findings across surveys, the panel found that the period, definition of disability, treatment of the institutionalized population, and age standardizing of results were important to consider. The implications of the findings for policy, national survey efforts, and further research are discussed.

%B Demography %I 41 %V 41 %P 417-41 %8 2004 Aug %G eng %N 3 %1 http://www.ncbi.nlm.nih.gov/pubmed/15461008?dopt=Abstract %4 Disability/Disability/ADL and IADL Impairments/Elderly/Caregiving %$ 12982 %R 10.1353/dem.2004.0022 %0 Journal Article %J American Sociological Review %D 2000 %T The Significance of Socioeconomic Status in Explaining the Racial Gap in Chronic Health Conditions %A Mark D Hayward %A Eileen M. Crimmins %A Toni Miles %A Yang, Yu %K Health Conditions and Status %K Net Worth and Assets %X Using Wave 1 (1992) and Wave 2 (1994) of the Health and Retirement Study the researchers try to detect the differences in life without health problems between different races so as to understand disparities in mortality rate and quality of life. Do Blacks have a higher risk of acquiring chronic health impairments of all types? How do differences in social conditions produce differences in the prevalence of fatal chronic diseases among races? The researchers notice that Blacks have a lower chance of surviving to middle age then do Whites. Blacks have a far greater level of morbidity in middle age, as well as, chances in having multiple fatal disease conditions. The author s give possible reasons for their findings, with much of it based on social status and life events. %B American Sociological Review %I 65 %V 65 %P 910-930 %G eng %L pubs_2000_Hayward_MASocR.pdf %4 Health Status/Economic Status %$ 8456 %R 10.2307/2657519