%0 Journal Article %J Epigenetics %D 2024 %T Epigenome-wide association study of long-term psychosocial stress in older adults. %A Opsasnick, Lauren A %A Zhao, Wei %A Schmitz, Lauren L %A Ratliff, Scott M %A Faul, Jessica D %A Zhou, Xiang %A Needham, Belinda L %A Smith, Jennifer A %K DNA Methylation %K Epigenome %K Smoking %K Stress, Psychological %K Tobacco Smoking %X

Long-term psychosocial stress is strongly associated with negative physical and mental health outcomes, as well as adverse health behaviours; however, little is known about the role that stress plays on the epigenome. One proposed mechanism by which stress affects DNA methylation is through health behaviours. We conducted an epigenome-wide association study (EWAS) of cumulative psychosocial stress ( = 2,689) from the Health and Retirement Study (mean age = 70.4 years), assessing DNA methylation (Illumina Infinium HumanMethylationEPIC Beadchip) at 789,656 CpG sites. For identified CpG sites, we conducted a formal mediation analysis to examine whether smoking, alcohol use, physical activity, and body mass index (BMI) mediate the relationship between stress and DNA methylation. Nine CpG sites were associated with psychosocial stress (all  < 9E-07; FDR q < 0.10). Additionally, health behaviours and/or BMI mediated 9.4% to 21.8% of the relationship between stress and methylation at eight of the nine CpGs. Several of the identified CpGs were in or near genes associated with cardiometabolic traits, psychosocial disorders, inflammation, and smoking. These findings support our hypothesis that psychosocial stress is associated with DNA methylation across the epigenome. Furthermore, specific health behaviours mediate only a modest percentage of this relationship, providing evidence that other mechanisms may link stress and DNA methylation.

%B Epigenetics %V 19 %P 2323907 %G eng %N 1 %R 10.1080/15592294.2024.2323907 %0 Journal Article %J Clin Epigenetics %D 2023 %T ADHD genetic burden associates with older epigenetic age: mediating roles of education, behavioral and sociodemographic factors among older adults. %A Arpawong, Thalida E %A Klopack, Eric T %A Jung K Kim %A Crimmins, Eileen M %K Aged %K Aging %K Attention Deficit Disorder with Hyperactivity %K Biomarkers %K DNA Methylation %K Educational Status %K Epigenesis, Genetic %K Humans %K Middle Aged %K sociodemographic factors %X

BACKGROUND: Shortened lifespans are associated with having Attention Deficit Hyperactivity Disorder (ADHD), which is likely mediated by related behavioral and sociodemographic factors that are also associated with accelerated physiological aging. Such factors include exhibiting more depressive symptoms, more cigarette smoking, higher body mass index, lower educational attainment, lower income in adulthood, and more challenges with cognitive processes compared to the general population. A higher polygenic score for ADHD (ADHD-PGS) is associated with having more characteristic features of ADHD. The degree to which (1) the ADHD-PGS associates with an epigenetic biomarker developed to predict accelerated aging and earlier mortality is unknown, as are whether (2) an association would be mediated by behavioral and sociodemographic correlates of ADHD, or (3) an association would be mediated first by educational attainment, then by behavioral and sociodemographic correlates. We evaluated these relationships in a population-based sample from the US Health and Retirement Study, among N = 2311 adults age 50 and older, of European-ancestry, with blood-based epigenetic and genetic data. The ADHD-PGS was calculated from a prior genomewide meta-analysis. Epigenome-wide DNA methylation levels that index biological aging and earlier age of mortality were quantified by a blood-based biomarker called GrimAge. We used a structural equation modeling approach to test associations with single and multi-mediation effects of behavioral and contextual indicators on GrimAge, adjusted for covariates.

RESULTS: The ADHD-PGS was significantly and directly associated with GrimAge when adjusting for covariates. In single mediation models, the effect of the ADHD-PGS on GrimAge was partially mediated via smoking, depressive symptoms, and education. In multi-mediation models, the effect of the ADHD-PGS on GrimAge was mediated first through education, then smoking, depressive symptoms, BMI, and income.

CONCLUSIONS: Findings have implications for geroscience research in elucidating lifecourse pathways through which ADHD genetic burden and symptoms can alter risks for accelerated aging and shortened lifespans, when indexed by an epigenetic biomarker. More education appears to play a central role in attenuating negative effects on epigenetic aging from behavioral and sociodemographic risk factors related to ADHD. We discuss implications for the potential behavioral and sociodemographic mediators that may attenuate negative biological system effects.

%B Clin Epigenetics %V 15 %P 67 %G eng %N 1 %R 10.1186/s13148-023-01484-y %0 Journal Article %J The Journals of Gerontology, Series B, Psychological Sciences and Social Sciences %D 2023 %T Associations Between Longitudinal Loneliness, DNA Methylation Age Acceleration, and Cognitive Functioning. %A Lynch, Morgan %A Em Arpawong, Thalida %A Beam, Christopher R %K Aged %K Aging %K Biomarkers %K Cognition %K DNA Methylation %K Humans %K Loneliness %K Longitudinal Studies %X

OBJECTIVES: Loneliness may influence aging biomarkers related to cognitive functioning, for example, through accelerated DNA methylation (DNAm) aging.

METHODS: In the present study, we tested whether six common DNAm age acceleration measures mediated the effects of baseline loneliness and five different longitudinal loneliness trajectories on general cognitive ability, immediate memory recall, delayed memory recall, and processing speed in 1,814 older adults in the Health and Retirement Study.

RESULTS: We found that baseline loneliness and individuals who belong to the highest loneliness trajectories had poorer general cognitive ability and memory scores. Only DNAm age acceleration measures that index physiological comorbidities, unhealthy lifestyle factors (e.g., smoking), and mortality risk-mediated effects of baseline loneliness on general cognitive ability and memory functioning but not processing speed. These same DNAm measures mediated effects of the moderate-but-declining loneliness trajectory on cognitive functioning. Additionally, immediate and delayed memory scores were mediated by GrimAge Accel in the lowest and two highest loneliness trajectory groups. Total and mediated effects of loneliness on cognitive functioning outcomes were mainly accounted for by demographic, social, psychological, and physiological covariates, most notably self-rated health, depressive symptomatology, objective social isolation, and body mass index.

DISCUSSION: Current findings suggest that DNAm biomarkers of aging, particularly GrimAge Accel, have promise for explaining the prospective association between loneliness and cognitive functioning outcomes.

%B The Journals of Gerontology, Series B, Psychological Sciences and Social Sciences %V 78 %P 2045-2059 %G eng %N 12 %R 10.1093/geronb/gbad128 %0 Journal Article %J Neurobiology & Aging %D 2023 %T A comparison of cognitive performances based on differing rates of DNA methylation GrimAge acceleration among older men and women. %A O'Shea, Deirdre M %A Alaimo, Hannah %A Davis, Jennifer D %A Galvin, James E %A Tremont, Geoffrey %K Aging %K Cognition %K DNA Methylation %K Executive function %K GrimAge %K Memory %K sex/gender differences %X

Cognitive heterogeneity increases with age rendering sex differences difficult to identify. Given established sex differences in biological aging, we examined whether comparisons of men and women on neuropsychological test performances differed as a function of age rate. Data were obtained from 1921 adults enrolled in the 2016 wave of the Health and Retirement Study. The residual from regressing the DNA methylation GrimAge clock on chronological age was used as the measure of aging rate. Slow and fast age rates were predefined as 1 standard deviation below or above the sex-specific mean rates, respectively. ANCOVAs were used to test group differences in test performances. Pairwise comparisons revealed that slow aging men outperformed fast aging women (and vice versa) on measures of executive function/speed, visual memory and semantic fluency; however, when groups were matched by aging rates, no significant differences remained. In contrast, women, regardless of their aging rates, education or depressive symptoms maintained their advantage on verbal learning and memory. Implications for research on sex differences in cognitive aging are discussed.

%B Neurobiology & Aging %V 123 %P 83-91 %G eng %R 10.1016/j.neurobiolaging.2022.12.011 %0 Journal Article %J Clin Epigenetics %D 2023 %T Epigenetic age acceleration mediates the association between smoking and diabetes-related outcomes. %A Chang, Xue-Yong %A Lin, Wan-Yu %K Aging %K Diabetes Mellitus %K DNA Methylation %K Epigenesis, Genetic %K Humans %K Plasminogen Activator Inhibitor 1 %K Smoking %X

BACKGROUND: Smoking can lead to the deterioration of lung function and susceptibility to diabetes. Recently, smoking was found to induce DNA methylation (DNAm) changes in some cytosine-phosphate-guanine sites (CpGs). As linear combinations of DNAm levels of aging-related CpGs, five measures of epigenetic age acceleration (EAA) have received extensive attention: HannumEAA, IEAA, PhenoEAA, GrimEAA, and DunedinPACE. It is of interest to explore whether some measures of EAA can mediate the associations of smoking with diabetes-related outcomes and indices of ventilatory lung function.

METHODS AND RESULTS: In this study, we included self-reported smoking variables (smoking status, the number of pack-years, and years since smoking cessation), seven DNAm markers (HannumEAA, IEAA, PhenoEAA, GrimEAA, DNAm-based smoking pack-years, DNAm plasminogen activator inhibitor 1 [PAI-1] levels, and DunedinPACE), and four health outcomes (fasting glucose, hemoglobin A1C, forced expiratory volume in 1.0 s [FEV1], and forced vital capacity [FVC]) from 2474 Taiwan Biobank participants. Mediation analyses were conducted while adjusting for chronological age, sex, body mass index, drinking status, regular exercise status, educational attainment, and five cell-type proportions. We demonstrated that GrimEAA, DNAm-based smoking pack-years, DNAm PAI-1 levels, DunedinPACE, and PhenoEAA mediated smoking associations with diabetes-related outcomes. Moreover, current and former smoking both had an adverse indirect effect on FVC through DNAm PAI-1 levels. For former smokers, a long time since smoking cessation had a positive indirect impact on FVC through GrimEAA and on FEV1 through PhenoEAA.

CONCLUSIONS: This is one of the first studies to comprehensively investigate the role of five measures of EAA in mediating the associations of smoking with the health outcomes of an Asian population. The results showed that the second-generation epigenetic clocks (GrimEAA, DunedinPACE, and PhenoEAA) significantly mediated the associations between smoking and diabetes-related outcomes. In contrast, the first-generation epigenetic clocks (HannumEAA and IEAA) did not significantly mediate any associations of smoking variables with the four health outcomes. Cigarette smoking can, directly and indirectly, deteriorate human health through DNAm changes in aging-related CpG sites.

%B Clin Epigenetics %V 15 %P 94 %G eng %N 1 %R 10.1186/s13148-023-01512-x %0 Journal Article %J PNAS %D 2023 %T Epigenetic-based age acceleration in a representative sample of older Americans: Associations with aging-related morbidity and mortality. %A Jessica Faul %A Jung K Kim %A Levine, Morgan E %A Bharat Thyagarajan %A David R Weir %A Eileen M. Crimmins %K Acceleration %K Aging %K Biomarkers %K Cross-Sectional Studies %K DNA Methylation %K Epigenesis %K genetic %X

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

%B PNAS %V 120 %P e2215840120 %G eng %N 9 %R 10.1073/pnas.2215840120 %0 Journal Article %J Journal of Cachexia, Sarcopenia and Muscle %D 2023 %T Grip strength is inversely associated with DNA methylation age acceleration. %A Peterson, Mark D %A Collins, Stacey %A Meier, Helen C S %A Brahmsteadt, Alexander %A Jessica Faul %K Ageing %K DNA Methylation %K Grip strength %K Strength training %X

BACKGROUND: There is a large body of evidence linking muscular weakness, as determined by low grip strength, to a host of negative ageing-related health outcomes. Given these links, grip strength has been labelled a 'biomarker of aging'; and yet, the pathways connecting grip strength to negative health consequences are unclear. The objective of this study was to determine whether grip strength was associated with measures of DNA methylation (DNAm) age acceleration.

METHODS: Middle age and older adults from the 2006 to 2008 waves of the Health and Retirement Study with 8-10 years of follow-up were included. Cross-sectional and longitudinal regression modelling was performed to examine the association between normalized grip strength (NGS) and three measures of DNAm age acceleration, adjusting for cell composition, sociodemographic variables and smoking. Longitudinal modelling was also completed to examine the association between change in absolute grip strength and DNAm age acceleration. The three DNAm clocks used for estimating age acceleration include the established DunedinPoAm, PhenoAge and GrimAge clocks.

RESULTS: There was a robust and independent cross-sectional association between NGS and DNAm age acceleration for men using the DunedinPoAm (β: -0.36; P < 0.001), PhenoAge (β: -8.27; P = 0.01) and GrimAge (β: -4.56; P = 0.01) clocks and for women using the DunedinPoAm (β: -0.36; P < 0.001) and GrimAge (β: -4.46; P = 0.01) clocks. There was also an independent longitudinal association between baseline NGS and DNAm age acceleration for men (β: -0.26; P < 0.001) and women (β: -0.36; P < 0.001) using the DunedinPoAm clock and for women only using the PhenoAge (β: -8.20; P < 0.001) and GrimAge (β: -5.91; P < 0.001) clocks. Longitudinal modelling revealed a robust association between change in grip strength from wave 1 to wave 3 was independently associated with PhenoAgeAA (β: -0.13; 95% CI: -0.23, -0.03) and GrimAgeAA (β: -0.07; 95% CI: -0.14, -0.01) in men only (both P < 0.05).

CONCLUSIONS: Our findings provide some initial evidence of age acceleration among men and women with lower NGS and loss of strength over time. Future research is needed to understand the extent to which DNAm age mediates the association between grip strength and chronic disease, disability and mortality.

%B Journal of Cachexia, Sarcopenia and Muscle %G eng %R 10.1002/jcsm.13110 %0 Journal Article %J Neurology %D 2023 %T Measures of Aging Biology in Saliva and Blood as Novel Biomarkers for Stroke and Heart Disease in Older Adults. %A Waziry, Reem %A Gu, Yian %A Boehme, Amelia K %A Williams, Olajide A %K Aged %K Aging %K Biology %K Biomarkers %K DNA Methylation %K Heart Diseases %K Humans %K Middle Aged %K Saliva %K Stroke %K United States %X

BACKGROUND AND OBJECTIVES: The role of aging biology as a novel risk factor and biomarker for vascular outcomes in different accessible body tissues such as saliva and blood remain unclear. We aimed to (1) assess the role of aging biology as a risk factor of stroke and heart disease among individuals of same chronologic age and sex and (2) compare aging biology biomarkers measured in different accessible body tissues as novel biomarkers for stroke and heart disease in older adults.

METHODS: This study included individuals who consented for blood and saliva draw in the Venous Blood Substudy and Telomere Length Study of the Health and Retirement Study (HRS). The HRS is a population-based, nationally representative longitudinal survey of individuals aged 50 years and older in the United States. Saliva-based measures included telomere length. Blood-based measures included DNA methylation and physiology biomarkers. Propensity scores-matched analyses and Cox regression models were conducted.

RESULTS: This study included individuals aged 50 years and older, who consented for blood (N = 9,934) and saliva (N = 5,808) draw in the HRS. Blood-based biomarkers of aging biology showed strong associations with incident stroke as follows: compared with the lowest tertile of blood-based biomarkers of aging, biologically older individuals had significantly higher risk of stroke based on DNA methylation Grim Age clock (adjusted hazard ratio [aHR] = 2.64, 95% CI 1.90-3.66, < 0.001) and Physiology-based Phenotypic Age clock (aHR = 1.75, 95% CI 1.27-2.42, < 0.001). In secondary analysis, biologically older individuals had increased risk of heart disease as follows: DNA methylation Grim Age clock (aHR = 1.77, 95% CI 1.49-2.11, < 0.001) and Physiology-based Phenotypic Age clock (aHR = 1.61, 95% CI 1.36-1.90, < 0.001).

DISCUSSION: Compared with saliva-based telomere length, blood-based aging physiology and some DNA methylation biomarkers are strongly associated with vascular disorders including stroke and are more precise and sensitive biomarkers of aging. Saliva-based telomere length and blood-based DNA methylation and physiology biomarkers likely represent different aspects of biological aging and accordingly vary in their precision as novel biomarkers for optimal vascular health.

%B Neurology %V 101 %P e2355-e2363 %G eng %N 23 %R 10.1212/WNL.0000000000207909 %0 Web Page %D 2023 %T New research highlights DNA methylation as noteworthy biomarker for epigenetic aging %A Meerdink, Jon %K biomarker %K DNA Methylation %K Epigenetic aging %I Michigan News, University of Michigan %G eng %U https://news.umich.edu/new-research-highlights-dna-methylation-as-noteworthy-biomarker-for-epigenetic-aging/ %0 Journal Article %J Epigenetics %D 2023 %T Occupational characteristics and epigenetic aging among older adults in the United States. %A Andrasfay, Theresa %A Crimmins, Eileen %K Aged %K Aging %K DNA Methylation %K Epigenesis, Genetic %K ethnicity %K Humans %K United States %X

Occupational characteristics have been studied as risk factors for several age-related diseases and are thought to impact the ageing process, although there has been limited empirical work demonstrating an association between adverse occupational characteristics and accelerated ageing and this prior work has yielded mixed results. We used the 2010 and 2016 waves of the Health and Retirement Study ( = 1,251) to examine the association between occupation categories and self-reported working conditions of American adults at midlife and their subsequent epigenetic ageing as measured through five epigenetic clocks: PCHorvath, PCHannum, PCPhenoAge, PCGrimAge, and DunedinPACE. We found that individuals working in sales/clerical, service, and manual work show evidence of epigenetic age acceleration compared to those working in managerial/professional jobs and that the associations were stronger with second- and third-generation clocks. Individuals reporting high stress and high physical effort at work showed evidence of epigenetic age acceleration only on PCGrimAge and DunedinPACE. Most of these associations were attenuated after adjustment for race/ethnicity, educational attainment, and lifestyle-related risk factors. Sales/clerical work remained significantly associated with PCHorvath and PCHannum, while service work remained significantly associated with PCGrimAge. The results suggest that manual work and occupational physical activity may appear to be risk factors for epigenetic age acceleration through their associations with socioeconomic status, while stress at work may be a risk factor for epigenetic age acceleration through its associations with health behaviours outside of work. Additional work is needed to understand when in the life course and the specific mechanisms through which these associations occur.

%B Epigenetics %V 18 %P 2218763 %G eng %N 1 %R 10.1080/15592294.2023.2218763 %0 Journal Article %J Psychoneuroendocrinology %D 2023 %T Positive social factors prospectively predict younger epigenetic age: Findings from the Health and Retirement Study. %A Hillmann, Abby R %A Dhingra, Roma %A Reed, Rebecca G %K Aging %K DNA Methylation %K Epigenesis %K genetic %K Retirement %K Social Factors %K Spouses %X

OBJECTIVES: Positive social factors may slow biological aging, but this has yet to be rigorously tested. This study investigated whether baseline levels or changes over time in social support and contact frequency prospectively predicted epigenetic age.

METHOD: Health and Retirement Study participants (N = 1912, 46.3 % male, aged 42-87 at baseline) reported longitudinal social support and contact frequency data up to 3 times between 2006 and 2016 and provided blood in 2016. Baseline levels (intercepts) and changes over time (slopes) in social support from and contact frequency with spouses, children, friends, and other family were outputted from multilevel models and used to predict epigenetic age, estimated from Horvath, Hannum, GrimAge, PhenoAge, and Dunedin Pace of Aging.

RESULTS: In models adjusted for demographic and health characteristics, higher baseline levels of support from and contact frequency with friends were prospectively associated with a slower Pace of Aging (support: p = .002; contact: p = 0.009) and a lower GrimAge (contact: p = .001). In addition, higher contact frequency with children at baseline was prospectively associated with a lower GrimAge (p < .001), and higher contact frequency with family at baseline and an increase in family contact over time was associated with a lower Hannum age (baseline: p = .005; slope: p = .015).

CONCLUSIONS: Perceived support from and contact with close others, particularly friends, may have implications for healthy biological aging. Notably, the effect sizes for friends were comparable to the effect of body mass index on epigenetic age. Positive social factors were generally associated with second- and third-generation clocks, which may be more sensitive to psychosocial factors than first-generation clocks.

%B Psychoneuroendocrinology %V 148 %P 105988 %G eng %R 10.1016/j.psyneuen.2022.105988 %0 Journal Article %J Psychoneuroendocrinology %D 2023 %T Reduced epigenetic age in older adults who volunteer. %A Nakamura, Julia S %A Kwok, Cherise %A Huang, Andrew %A Strecher, Victor J %A Kim, Eric S %A Cole, Steven W %K DNA Methylation %K Epigenetic age acceleration %K Health behaviors %K Volunteering %X

BACKGROUND: Volunteering is associated with improved health and well-being outcomes, including a reduced risk of mortality. However, the biological mechanisms underlying the association between volunteering and healthy aging and longevity have not been well-established. We evaluated if volunteering was associated with reduced epigenetic age acceleration in older adults.

METHODS: We evaluated associations between volunteering and age acceleration, measured by 13 DNA methylation (DNAm) "epigenetic clocks" in 4011 older adults (M=69 years; SD=10 years) who participated in the Health and Retirement Study. We assessed 9 first-generation clocks (Horvath, Hannum, Horvath Skin, Lin, Garagnani, Vidalbralo, Weidner, Yang, and Bocklandt, which predict chronological age) and 4 second-generation clocks (Zhang, PhenoAge, GrimAge, and DunedinPoAm, which predict future disease or longevity). We quantified the total associations between volunteering and DNAm age acceleration as well as the extent to which these associations might be attributable to potential confounding by individual demographics (e.g., race), social demographics (e.g., income), health factors (e.g., diabetes), and health behaviors (e.g., smoking).

RESULTS: Volunteering was associated with reduced epigenetic age acceleration across 6 epigenetic clocks optimized for predicting health and longevity (False Discovery Rate [FDR] q < 0.0001 for epigenetic clocks: PhenoAge, GrimAge, DunedinPoAm, Zhang mortality, Yang mitotic; FDR q < 0.01: Hannum). These associations were mostly independent of demographic and health factors, but substantially attenuated after adjusting for health behaviors.

CONCLUSION: Volunteering was associated with reduced epigenetic age acceleration in 6 of 13 (mostly second-generation) epigenetic clocks. Results provide preliminary evidence that volunteering might provide health benefits through slower biological aging and implicate health behaviors as one potential mechanism of such effects.

%B Psychoneuroendocrinology %V 148 %P 106000 %G eng %R 10.1016/j.psyneuen.2022.106000 %0 Journal Article %J Brain, behavior and immunity %D 2023 %T Social relationships and epigenetic aging in older adulthood: Results from the Health and Retirement Study. %A Rentscher, Kelly E %A Klopack, Eric T %A Crimmins, Eileen M %A Seeman, Teresa E %A Cole, Steve W %A Carroll, Judith E %K biological aging %K DNA Methylation %K epigenetic clock %K Social Relationships %K Social strain %K Social Support %X

Growing evidence suggests that social relationship quality can influence age-related health outcomes, although how the quality of one's relationships directly relates to the underlying aging process is less clear. We hypothesized that the absence of close relationships as well as lower support and higher strain within existing relationships would be associated with an accelerated epigenetic aging profile among older adults in the Health and Retirement Study. Adults (N = 3,647) aged 50-100 years completed ratings of support and strain in relationships with their spouse, children, other family members, and friends. They also provided a blood sample that was used for DNA methylation profiling to calculate a priori-specified epigenetic aging measures: Horvath, Hannum, PhenoAge, GrimAge, and Dunedin Pace of Aging methylation (DunedinPoAm38). Generalized linear models that adjusted for chronological age, sex, and race/ethnicity and applied a false discovery rate correction revealed that the absence of marital and friend relationships related to an older GrimAge and faster DunedinPoAm38. Among those with existing relationships, lower support from a spouse, child, other family, and friends and higher strain with friends related to an older PhenoAge and GrimAge and faster DunedinPoAm38. In secondary analyses that further adjusted for socioeconomic and lifestyle factors, lower support from other family members and friends was associated with greater epigenetic aging. Findings suggest that the absence of close relationships and lower support within existing relationships-particularly with family members and friends-relate to accelerated epigenetic aging in older adulthood, offering one mechanism through which social relationships might influence risk for age-related declines and disease.

%B Brain, behavior and immunity %V 114 %P 349-359 %G eng %R 10.1016/j.bbi.2023.09.001 %0 Journal Article %J Geroscience %D 2023 %T Systemic inflammation and biological aging in the Health and Retirement Study. %A Meier, Helen C S %A Mitchell, Colter %A Karadimas, Thomas %A Jessica Faul %K Aging %K Biomarkers %K DNA Methylation %K Epigenesis, Genetic %K Humans %K Inflammation %K Retirement %X

Chronic, low-level systemic inflammation associated with aging, or inflammaging, is a risk factor for several chronic diseases and mortality. Using data from the Health and Retirement Study, we generated a continuous latent variable for systemic inflammation from seven measured indicators of inflammation and examined associations with another biomarker of biological aging, DNA methylation age acceleration measured by epigenetic clocks, and 4-year mortality (N = 3,113). We found that greater systemic inflammation was positively associated with DNA methylation age acceleration for 10 of the 13 epigenetic clocks, after adjustment for sociodemographics and chronic disease risk factors. The latent variable for systemic inflammation was associated with 4-year mortality independent of DNA methylation age acceleration and was a better predictor of 4-year mortality than any of the epigenetic clocks examined, as well as mortality risk factors, including obesity and multimorbidity. Inflammaging and DNA methylation age acceleration may represent different biological processes contributing to mortality risk. Leveraging multiple measured inflammation markers to capture inflammaging is important for biology of aging research.

%B Geroscience %V 45 %P 3257-3265 %G eng %N 6 %R 10.1007/s11357-023-00880-9 %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 The Journals of Gerontology, Series A %D 2022 %T DNA methylation "GrimAge" acceleration mediates sex/gender differences in verbal memory and processing speed: Findings from the Health and Retirement Study. %A O'Shea, Deirdre M %A Maynard, Taylor %A Tremont, Geoffrey %K Biological age %K Cognition %K DNA Methylation %K GrimAge %K HCAP %K sex/gender differences %X

Whether sex/gender differences in rates of biological aging mediate sex/gender differences in cognition in older adults has not been fully examined. The aim of the current study was to investigate this association. Data from up to 1,928 participants (mean age = 75, SD = 7.04, female = 57%) who took part in the 2016 Harmonized Cognitive Assessment Protocol and Venous Blood Study; sub-studies of the Health and Retirement Study were included in the current study. The residuals from four age-adjusted epigenetic clocks (Horvath, Hannum, PhenoAge, and GrimAge) were used to measure biological age acceleration. Sex/gender differences in cognition were tested using a series of ANCOVAs. Mediation analyses tested whether the measures of age acceleration accounted for these sex/gender differences, controlling for age, education, smoking status, and white blood cell count. Women outperformed men on measures of verbal learning, verbal memory, visual scanning, and processing speed. No other significant sex/gender differences were identified. Results from mediation analyses revealed that women's slower rates of GrimAge fully accounted for their faster processing speeds and partially accounted for their better performances on verbal learning, verbal memory, and visual scanning measures. None of the other measures of age acceleration were significant mediators. Accounting for sex/gender differences in biological aging may differentiate between cognitive sex/gender differences that are driven by universal (i.e., age-related) versus sex-specific mechanisms. More broadly, these findings support the growing evidence that the GrimAge clock outperforms other clocks in predicting cognitive outcomes.

%B The Journals of Gerontology, Series A %G eng %R 10.1093/gerona/glac133 %0 Journal Article %J Aging %D 2022 %T Epigenetic clocks and their association with trajectories in perceived discrimination and depressive symptoms among US middle-aged and older adults. %A Beydoun, May A %A Beydoun, Hind A %A Noren Hooten, Nicole %A Maldonado, Ana I %A Weiss, Jordan %A Evans, Michele K %A Zonderman, Alan B %K Biological age %K Depressive symptoms %K DNA Methylation %K epigenetic clocks %K Perceived Discrimination %X

BACKGROUND: Perceived discrimination may be associated with accelerated aging later in life, with depressive symptoms acting as potential mediator.

METHODS: A nationally representative sample of older adults was used [Health and Retirement Study 2010-2016, Age: 50-100 y in 2016, = 2,806, 55.6% female, 82.3% Non-Hispanic White (NHW)] to evaluate associations of perceived discrimination measures [Experience of discrimination or EOD; and Reasons for Perceived discrimination or RPD) and depressive symptoms (DEP)] with 13 DNAm-based measures of epigenetic aging. Group-based trajectory and four-way mediation analyses were used.

RESULTS: Overall, and mostly among female and NHW participants, greater RPD in 2010-2012 had a significant adverse total effect on epigenetic aging [2016: DNAm GrimAge, DunedinPoAm38 (MPOA), Levine (PhenoAge) and Horvath 2], with 20-50% of this effect being explained by a pure indirect effect through DEP in 2014-2016. Among females, sustained elevated DEP (2010-2016) was associated with greater LIN DNAm age (β ± SE: +1.506 ± 0.559, = 0.009, reduced model), patterns observed for elevated DEP (high vs. low) for GrimAge and MPOA DNAm markers. Overall and in White adults, the relationship of the Levine clock with perceived discrimination in general (both EOD and RPD) was mediated through elevated DEP.

CONCLUSIONS: Sustained elevations in DEP and RPD were associated with select biological aging measures, consistently among women and White adults, with DEP acting as mediator in several RPD-EPICLOCK associations.

%B Aging %V 14 %P 5311—5344 %G eng %N 13 %R 10.18632/aging.204150 %0 Journal Article %J PNAS %D 2022 %T In utero exposure to the Great Depression is reflected in late-life epigenetic aging signatures. %A Schmitz, Lauren L %A Duque, Valentina %K Aging %K DNA Methylation %K Epigenesis %K Epigenomics %K genetic %K Great Depression %K Prenatal Exposure Delayed Effects %X

Research on maternal-fetal epigenetic programming argues that adverse exposures to the intrauterine environment can have long-term effects on adult morbidity and mortality. However, causal research on epigenetic programming in humans at a population level is rare and is often unable to separate intrauterine effects from conditions in the postnatal period that may continue to impact child development. In this study, we used a quasi-natural experiment that leverages state-year variation in economic shocks during the Great Depression to examine the causal effect of environmental exposures in early life on late-life accelerated epigenetic aging for 832 participants in the US Health and Retirement Study (HRS). HRS is the first population-representative study to collect epigenome-wide DNA methylation data that has the sample size and geographic variation necessary to exploit quasi-random variation in state environments, which expands possibilities for causal research in epigenetics. Our findings suggest that exposure to changing economic conditions in the 1930s had lasting impacts on next-generation epigenetic aging signatures that were developed to predict mortality risk (GrimAge) and physiological decline (DunedinPoAm). We show that these effects are localized to the in utero period specifically as opposed to the preconception, postnatal, childhood, or early adolescent periods. After evaluating endogenous shifts in mortality and fertility related to Depression-era birth cohorts, we conclude that these effects likely represent lower bound estimates of the true impacts of the economic shock on long-term epigenetic aging.

%B PNAS %V 119 %P e2208530119 %G eng %N 46 %R 10.1073/pnas.2208530119 %0 Journal Article %J Genes %D 2022 %T The Interplay of Epigenetic, Genetic, and Traditional Risk Factors on Blood Pressure: Findings from the Health and Retirement Study. %A Zhang, Xinman %A Ammous, Farah %A Lin, Lisha %A Ratliff, Scott M %A Ware, Erin B %A Jessica Faul %A Zhao, Wei %A Sharon L R Kardia %A Smith, Jennifer A %K Blood pressure %K DNA Methylation %K genetic risk score %K Genetics %K interaction %K methylation risk score. %X

The epigenome likely interacts with traditional and genetic risk factors to influence blood pressure. We evaluated whether 13 previously reported DNA methylation sites (CpGs) are associated with systolic (SBP) or diastolic (DBP) blood pressure, both individually and aggregated into methylation risk scores (MRS), in 3070 participants (including 437 African ancestry (AA) and 2021 European ancestry (EA), mean age = 70.5 years) from the Health and Retirement Study. Nine CpGs were at least nominally associated with SBP and/or DBP after adjusting for traditional hypertension risk factors ( < 0.05). MRS was positively associated with SBP in the full sample (β = 1.7 mmHg per 1 standard deviation in MRS; = 2.7 × 10) and in EA (β = 1.6; = 0.001), and MRS with DBP in the full sample (β = 1.1; = 1.8 × 10), EA (β = 1.1; = 7.2 × 10), and AA (β = 1.4; = 0.03). The MRS and BP-genetic risk scores were independently associated with blood pressure in EA. The effects of both MRSs were weaker with increased age ( < 0.01), and the effect of MRS was higher among individuals with at least some college education ( = 0.02). In AA, increasing MRS was associated with higher SBP in females only ( = 0.01). Our work shows that MRS is a potential biomarker of blood pressure that may be modified by traditional hypertension risk factors.

%B Genes %V 13 %P 1959 %G eng %N 11 %R 10.3390/genes13111959 %0 Journal Article %J Clinical Epigenetics %D 2022 %T Lifetime exposure to smoking, epigenetic aging, and morbidity and mortality in older adults. %A Klopack, Eric T %A Carroll, Judith E %A Cole, Steve W %A Seeman, Teresa E %A Eileen M. Crimmins %K DNA Methylation %K Epigenesis %K genetic %K Morbidity %K Smoking %K Tobacco %K Venous Blood Study %X

BACKGROUND: Cigarette smoke is a major public health concern. Epigenetic aging may be an important pathway by which exposure to cigarette smoke affects health. However, little is known about how exposure to smoke at different life stages affects epigenetic aging, especially in older adults. This study examines how three epigenetic aging measures (GrimAge, PhenoAge, and DunedinPoAm38) are associated with parental smoking, smoking in youth, and smoking in adulthood, and whether these epigenetic aging measures mediate the link between smoke exposure and morbidity and mortality. This study utilizes data from the Health and Retirement Study (HRS) Venous Blood Study (VBS), a nationally representative sample of US adults over 50 years old collected in 2016. 2978 participants with data on exposure to smoking, morbidity, and mortality were included.

RESULTS: GrimAge is significantly increased by having two smoking parents, smoking in youth, and cigarette pack years in adulthood. PhenoAge and DunedinPoAm38 are associated with pack years. All three mediate some of the effect of pack years on cancer, high blood pressure, heart disease, and mortality and GrimAge and DunedinPoAm38 mediate this association on lung disease.

CONCLUSIONS: Results suggest epigenetic aging is one biological mechanism linking lifetime exposure to smoking with development of disease and earlier death in later life. Interventions aimed at reducing smoking in adulthood may be effective at weakening this association.

%B Clinical Epigenetics %V 14 %P 72 %G eng %N 1 %R 10.1186/s13148-022-01286-8 %0 Journal Article %J Alzheimer's & Dementia %D 2022 %T Social epigenetics of racial disparities in aging %A Yannatos, Isabel %A Xie, Sharon X %A Brown, Rebecca %A McMillan, Corey T %K Aging %K DNA Methylation %K epigenetics %K Racial Disparities %X Racial disparities in many aging-related health outcomes are persistent and pervasive among older Americans. There are well-documented inequities in the social determinants of health for older adults, including the social and physical environment, due to structural and environmental racism, but there is little understanding of the biological intermediates by which social determinants affect disparate health outcomes. Biological aging measured by DNA methylation (DNAm) is robustly associated with worse age-related outcomes and higher social adversity. We hypothesize that individual social determinants, the social environment, and air pollution exposures interact to contribute to racial disparities in DNAm aging according to GrimAge and Dunedin Pace of Aging methylation (DPoAm). Method We performed retrospective cross-sectional analyses among 3250 non-Hispanic participants (80.3% white, 19.7% Black) in the Health and Retirement Study whose 2016 epigenetic age is linked to survey responses and geographic data. DNAm aging is defined as the residual after regressing epigenetic age on chronological age. Measures of the neighborhood social environment include the Social Deprivation Index and perceived social stress. Air pollution exposures include particulate matter (PM2.5), nitrogen dioxide (NO2), and ozone. Individual-level determinants include socioeconomic status, healthcare access, health status, and health behaviors. We implemented multivariable linear regression models to identify significant associations, interactions, and mediators in the relationship between each DNAm aging measure and the social and environmental determinants. Result We found on average Black individuals have significantly accelerated DNAm aging compared to white individuals (599% and 498%) according to GrimAge and DPoAm, respectively. Individual-level factors evaluated account for approximately 43% of the disparity in GrimAge and 34% in DPoAm. Further results suggest that associations between neighborhood social environment and DNAm aging are significant and mediated by individual-level factors. PM2.5 may be associated with DPoAm acceleration in certain sub-populations. NO2 and ozone are not significantly associated with DNAm aging. We are investigating individual-level factors that mediate social environmental exposures and increase vulnerability to PM2.5. Conclusion DNAm aging may play a role in social determinants “getting under the skin” and contributing to age-related health disparities between Black and white Americans. Work is ongoing to determine the environmental and individual factors that contribute to these disparities. %B Alzheimer's & Dementia %V 18 %P e067179 %G eng %N S11 %R 10.1002/alz.067179 %0 Journal Article %J Neurology %D 2022 %T Socioeconomic Status, Biological Aging, and Memory in a Diverse National Sample of Older US Men and Women. %A Avila-Rieger, Justina %A Turney, Indira C %A Vonk, Jet M J %A Esie, Precious %A Seblova, Dominika %A Weir, Vanessa R %A Belsky, Daniel W %A Jennifer J Manly %K biological aging %K Cognition %K DNA Methylation %K Race/ethnicity %K sex/gender %K socio-economic status %X

BACKGROUND AND OBJECTIVES: Exposure to socioeconomic disadvantage is associated with early-onset cognitive aging. Biological aging, the progressive loss of system integrity that occurs as we age is proposed as a modifiable process mediating this health inequality. We examined whether socioeconomic disparities in cognitive aging in mid-to late-life adults is explained by accelerated biological aging similarly across race, ethnicity and sex/gender.

METHODS: Data was from a prospective cohort study of the U.S. Health and Retirement Study DNA-methylation sub-study. Socioeconomic status (SES) was measured from years of education and household wealth at baseline. The extent and pace of biological aging were quantified using three DNA-methylation measures: PhenoAge, GrimAge, and DunedinPoAm. Cognitive aging was measured from repeated longitudinal assessments of immediate and delayed word recall. Latent growth curve modeling estimated participants' level of memory performance and rate of decline over 2-11 follow-up assessments spanning 2-20 years. Multiple-group models were estimated to assess whether the relationship between SES and memory trajectories was mediated by biological aging across racial-ethnic by sex/gender subgroups.

RESULTS: Data from a total of 3,997 adults aged 50-100 were analyzed. Participants with lower SES had lower memory performance, faster decline and exhibited accelerated biological aging (SES effect size associations (β) ranged from .08 to .41). Accelerated biological aging was associated with decreased memory performance and faster memory decline (effect-size range .03 to .23). SES-biological aging associations were strongest for White men and women and weakest for Latinx women. The relationship between biological aging measures and memory was weaker for Black participants compared with White and Latinx people. In mediation analysis, biological aging accounted for 4-27% of the SES-memory gradient in White participants. There was little evidence of mediation in Black or Latinx participants.

DISCUSSION: Among a national sample of mid-to late-life adults, DNA-methylation measures of biological aging were variably associated with memory trajectories and SES across White, Black, and Latinx mid-to late-life adults. These results challenge the assumption that DNA-methylation biomarkers of aging that were developed in primarily White people can equivalently quantify aging processes affecting cognition in Black and Latinx mid-to late-life adults.

%B Neurology %V 99 %P e2114-e2124 %G eng %N 19 %R 10.1212/WNL.0000000000201032 %0 Journal Article %J American Journal of Epidemiology %D 2022 %T Testing Black-White Disparities in Biological Aging Among Older Adults in the United States: Analysis of DNA-Methylation and Blood-Chemistry Methods. %A Graf, Gloria H %A Crowe, Christopher L %A Kothari, Meeraj %A Kwon, Dayoon %A Jennifer J Manly %A Turney, Indira C %A Valeri, Linda %A Belsky, Daniel W %K Activities of Daily Living %K Cross-Sectional Studies %K DNA %K DNA Methylation %X

Biological aging is a proposed mechanism through which social determinants drive health disparities. We conducted proof-of-concept testing of 8 DNA-methylation (DNAm) and blood-chemistry quantifications of biological aging as mediators of disparities in healthspan between Black and White participants in the 2016 wave of the Health and Retirement Study (n = 9,005). We quantified biological aging from 4 DNAm "clocks" (Horvath, Hannum, PhenoAge, and GrimAge clock), a DNAm pace-of-aging measure (DunedinPoAm), and 3 blood-chemistry measures (PhenoAge, Klemera-Doubal method biological age, and homeostatic dysregulation). We quantified Black-White disparities in healthspan from cross-sectional and longitudinal data on physical performance tests, self-reported limitations in activities of daily living, and physician-diagnosed chronic diseases, self-rated health, and survival. DNAm and blood-chemistry quantifications of biological aging were moderately correlated (Pearson's r = 0.1-0.4). The GrimAge clock, DunedinPoAm, and all 3 blood-chemistry measures were associated with healthspan characteristics (e.g., mortality effect-size hazard ratios were 1.71-2.32 per standard deviation of biological aging) and showed evidence of more advanced/faster biological aging in Black participants than in White participants (Cohen's d = 0.4-0.5). These measures accounted for 13%-95% of Black-White differences in healthspan-related characteristics. Findings suggest that reducing disparities in biological aging can contribute to building health equity.

%B American Journal of Epidemiology %V 191 %P 613-625 %G eng %N 4 %R 10.1093/aje/kwab281 %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 The Journals of Gerontology: Series A %D 2021 %T Associations of Age, Sex, Race/Ethnicity and Education with 13 Epigenetic Clocks in a Nationally Representative US Sample: The Health and Retirement Study. %A Eileen M. Crimmins %A Bharat Thyagarajan %A Morgan E. Levine %A David R Weir %A Jessica Faul %K DNA Methylation %K DunedinPoAm38 %K Epigenetic Age %K GrimAge %K PhenoAgeAcceleration %X

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.

%B The Journals of Gerontology: Series A %V 76 %P 1117-1123 %G eng %N 6 %R 10.1093/gerona/glab016 %0 Journal Article %J Alzheimer's & Dementia %D 2021 %T Chronic loneliness-by-epigenetic age effects on dementia risk in late adulthood %A Lynch, Morgan E %A Beam, Christopher R %K Biological age %K dementia risk %K DNA Methylation %K Loneliness %X Background Over the last 10 years, numerous studies have been published reporting a small but significant correlation between loneliness and dementia risk. To date, few studies have tested mechanisms that mediate the longitudinal association between loneliness and dementia. DNA methylation may be one variable that explains this association, as when combined with other biomarkers, quantifies whether people’s biological age is more (or less) advanced than their chronological age. The purpose of this study is to test whether epigenetic age moderates the longitudinal trajectory of loneliness on dementia risk. Method The sample was drawn from the three waves of the Health and Retirement Study (n = 268, mean age = 69) collected four years apart from 2008-2016. Loneliness scores were composed using with 11 items of the UCLA Loneliness Questionnaire. Dementia risk was quantified according to Langa-Weir’s approach that uses the modified Telephone Interview for Cognitive Status. Epigenetic age is quantified by DNAm PhenoAge (Levine et al., 2015.). Ordinary least squares regression was used to test the interaction effect of DNAm PhenoAge and loneliness on dementia risk. Result A significant interaction effect between DNAmPhenoAge and longitudinal loneliness on dementia risk was found (F(7,268) = 6.98 , p < 0.001; adjusted R2 =.13). Effects of DNAm PhenoAge were greater in those with higher levels of loneliness over time, suggesting that effects of loneliness on dementia risk depend on epigenetic age. Conclusion Study results suggest that the longitudinal association between loneliness and dementia risk depends on epigenetic age. One implication of the current results is that the epigenome may be a promising area of study for understanding the processes through which loneliness increases dementia risk. %B Alzheimer's & Dementia %V 17 %P e050968 %G eng %R 10.1002/alz.050968 %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 The Journals of Gerontology, Series A %D 2021 %T Feature selection algorithms enhance the accuracy of frailty indexes as measures of biological age. %A Kim, Sangkyu %A Fuselier, Jessica %A Welsh, David A %A Cherry, Katie E %A Myers, Leann %A Jazwinski, S Michal %K Biological age %K DNA Methylation %K frailty index %K Mortality %X

Biological age captures some of the variance in life expectancy for which chronological age is not accountable, and it quantifies the heterogeneity in the presentation of the aging phenotype in various individuals. Among the many quantitative measures of biological age, the mathematically uncomplicated frailty/deficit index is simply the proportion of the total health deficits in various health items surveyed in different individuals. We used three different statistical methods that are popular in machine learning to select 17-28 health items that together are highly predictive of survival/mortality, from independent study cohorts. From the selected sets, we calculated frailty indexes and Klemera-Doubal's biological age estimates, and then compared their mortality prediction performance using Cox proportional hazards regression models. Our results indicate that the frailty index outperforms age and Klemera-Doubal's biological age estimates, especially among the oldest old who are most prone to biological aging-caused mortality. We also showed that a DNA methylation index, which was generated by applying the frailty/deficit index calculation method to 38 CpG sites that were selected using the same machine learning algorithms, can predict mortality even better than the best performing frailty index constructed from health, function, and blood chemistry.

%B The Journals of Gerontology, Series A %V 76 %P 1347-1355 %G eng %N 8 %R 10.1093/gerona/glab018 %0 Journal Article %J Elife %D 2019 %T Genomics of 1 million parent lifespans implicates novel pathways and common diseases and distinguishes survival chances. %A Paul Rhj Timmers %A Mounier, Ninon %A Lall, Kristi %A Fischer, Krista %A Ning, Zheng %A Feng, Xiao %A Bretherick, Andrew D %A Clark, David W %A Shen, Xia %A Tõnu Esko %A Kutalik, Zoltán %A James F Wilson %A Joshi, Peter K %K Age Factors %K Aged %K Bayes Theorem %K Disease %K DNA Methylation %K Female %K Genetic Loci %K Genome-Wide Association Study %K Genomics %K Humans %K Longevity %K Male %K Middle Aged %K Multifactorial Inheritance %K Parents %K Polymorphism, Single Nucleotide %K Risk Factors %K Sex Characteristics %K Signal Transduction %K Survival Analysis %X

We use a genome-wide association of 1 million parental lifespans of genotyped subjects and data on mortality risk factors to validate previously unreplicated findings near , , , , , and 13q21.31, and identify and replicate novel findings near , , and . We also validate previous findings near 5q33.3/ and , whilst finding contradictory evidence at other loci. Gene set and cell-specific analyses show that expression in foetal brain cells and adult dorsolateral prefrontal cortex is enriched for lifespan variation, as are gene pathways involving lipid proteins and homeostasis, vesicle-mediated transport, and synaptic function. Individual genetic variants that increase dementia, cardiovascular disease, and lung cancer - but not other cancers - explain the most variance. Resulting polygenic scores show a mean lifespan difference of around five years of life across the deciles.

Editorial note: This article has been through an editorial process in which the authors decide how to respond to the issues raised during peer review. The Reviewing Editor's assessment is that all the issues have been addressed (see decision letter).

%B Elife %V 8 %P e39856 %G eng %R 10.7554/eLife.39856