Measures Of Epigenetic Age Acceleration Research Articles

Loneliness, epigenetic age acceleration, and chronic health conditions.

Having associations with a range of adverse physical health outcomes including mortality, loneliness is increasingly recognized as a pressing public health concern, but the mechanisms studied to date do not yet explain all loneliness-related health risk. We sought to evaluate whether epigenetic influences on DNA methylation could help explain the relationship between loneliness and health. To do so, we first estimated associations between loneliness and epigenetic age acceleration (EAA) in a subsample of participants in the study of midlife in the United States (n = 1,310), before testing whether EAA mediated and/or moderated the association between loneliness and the onset of chronic health conditions in older adulthood (n = 445 completing longitudinal follow-ups). Greater loneliness was weakly associated with greater EAA in the Horvath, DunedinPACE, and GrimAge measures after accounting for demographic (0.08 ≤ β ≤ 0.11) and behavioral (0.06 ≤ β ≤ 0.08) covariates. Loneliness also predicted increases in chronic condition counts and these effects were more pronounced for individuals with higher DunedinPACE EAA values (interaction term β = 0.09, p = .009), suggesting possible synergistic impacts. EAA measures appear to be promising in helping to understand individual variations in the health impacts of loneliness, but the specific mechanisms involved require further research. (PsycInfo Database Record (c) 2024 APA, all rights reserved).

A Comparison of 5 Measures of Accelerated Biological Aging and Their Association With Incident Cardiovascular Disease: The CARDIA Study.

Accelerated biological aging is an increasingly popular way to track the acceleration of biology over time that may not be captured by calendar time. Biological aging has been linked to external and internal chronic stressors and has the potential to be used clinically to understand a person's personalized functioning and predict future disease. We compared the association of different measures of biological aging and incident cardiovascular disease (CVD) overall and by race. We used multiple informants models to compare the strength of clinical marker-derived age acceleration, 5 measures of epigenetic age acceleration (intrinsic and extrinsic epigenetic age acceleration, GrimAge acceleration, and PhenoAge acceleration), and 1 established clinical predictor of future CVD, Framingham 10-year risk score, with incident CVD over an 11-year period (2007-2018). Participants were 913 self-identified Black or White (41% and 59%, respectively) female or male (51% and 49%, respectively) individuals enrolled in the US-based CARDIA (Coronary Artery Risk Development in Young Adults) cohort study. The analytic baseline for this study was the 20-year follow-up examination (2005-2006; median age 45 years). We also included race-specific analysis. We found that all measures were modestly correlated with one another. However, clinical marker-derived age acceleration and Framingham 10-year risk score were more strongly associated with incident CVD than all the epigenetic measures. Clinical marker-derived age acceleration and Framingham 10-year risk score were not significantly different than one another in their association with incident CVD. The type of accelerated aging measure should be taken into consideration when comparing their association with clinical outcomes. A multisystem clinical composite shows associations with incident CVD equally to a well-known clinical predictor.

Abstract P413: Epigenetic Age Acceleration Measures Predict Cardiovascular Outcomes in Diabetic Kidney Disease

Introduction: Cardiovascular disease (CVD) remains the leading cause of mortality in the US, highlighting the need for novel approaches to its prediction, prevention, and management. Epigenetic age acceleration (EAA), or increased DNA methylation-based age relative to chronological age, is a promising biomarker of disease risk. While previous studies have prospectively linked EAA to CVD, recent work in patients with end-stage kidney disease showed no association between EAA and mortality from CVD, underscoring a need for more research across patient populations. Hypothesis: EAA measures, specifically intrinsic epigenetic age acceleration (IEAA), extrinsic epigenetic age acceleration (EEAA), phenotypic epigenetic age acceleration (PhenoAA), and Grim epigenetic age acceleration (GrimAA), are associated with incident CVD in diabetic kidney disease (DKD). Methods: In a subset of 496 participants from the Chronic Renal Insufficiency Cohort with DKD, selected based on kidney function decline over follow-up (large versus small), we examined four EAA measures: IEAA, EEAA, PhenoAA, and GrimAA. GrimAA is comprised of eight DNA methylation-based biomarkers, including plasminogen activator inhibitor-1 age acceleration (PAI-1 AA ) and tissue inhibitor of matrix metalloproteinase (TIMP-1 AA ), which were also assessed. Primary outcomes were incident CVD, atherosclerotic CVD, and CVD mortality; secondary outcomes included myocardial infarction, congestive heart failure (CHF), cerebrovascular accident, and peripheral artery disease (PAD). Cox proportional models tested associations between the EAA measures and CVD endpoints after adjusting for baseline demographics, clinical center, kidney function decline as a study design feature, lifestyle, and clinical risk factors. Results: Participants were predominantly male (63%), with a median age of 57 years, median eGFR of 44 mL/min/1.73m 2 , and mean hemoglobin A1c of 8.0%. After adjusting for multiple testing, each standard deviation increase in GrimAA was associated with incident CVD (HR=1.27; 95% confidence interval [CI], 1.08-1.50; p=0.012) and PAD (HR=1.65; 95% CI, 1.15-2.37; p=0.006). Likewise, PAI-1 AA was significantly associated with incident CVD (HR=1.24; 95% CI, 1.06-1.44; p=0.006) and PAD (HR=1.46; 95% CI, 1.17-1.81; p=0.001), while TIMP-1 AA was associated with CHF (HR=1.32; 95% CI, 1.09-1.60; p=0.005). Nominally significant associations between IEAA and atherosclerotic CVD were also identified (HR=1.24; 95% CI, 1.00-1.53; p=0.049). Similarly, EEAA was nominally associated with incident CVD (HR 1.22; 95% CI, 1.01-1.47, p=0.039). Conclusion: EAA measures, notably GrimAA, are promising CVD biomarkers in DKD patients. Associations of GrimAA components PAI-1 AA and TIMP-1 AA with incident CVD add to the accumulating evidence of their predictive and therapeutic potential.

Assessing the association of epigenetic age acceleration with osteoarthritis in the Multicenter Osteoarthritis Study (MOST)

PurposeAdvancing age is one of the strongest risk factors for osteoarthritis (OA). DNA methylation-based measures of epigenetic age acceleration may provide insights into mechanisms underlying OA. MethodsWe analyzed data from the Multicenter Osteoarthritis Study (MOST) in a subset of 671 participants ages 45-69 years with no or mild radiographic knee OA. DNA methylation was assessed with the Illumina Infinium MethylationEPIC 850K array. We calculated predicted epigenetic age according to Hannum, Horvath, PhenoAge, and GrimAge epigenetic clocks, then regressed epigenetic age on chronological age to obtain the residuals. Associations between the residuals and knee, hand, and multi-joint OA were assessed using logistic regression, adjusted for chronological age, sex, clinical site, smoking status, and race. ResultsTwenty three percent met criteria for radiographic hand OA, 25% met criteria for radiographic knee OA, and 8% met criteria for multi-joint OA. Mean chronological age (SD) was 58.4 (6.7) years. Mean predicted epigenetic age (SD) according to Horvath, Hannum, PhenoAge, and GrimAge epigenetic clocks was 64.9 (6.4), 68.6 (5.9), 50.5 (7.7), and 67.0 (6.2), respectively. Horvath epigenetic age acceleration was not associated with an increased odds of hand OA, OR (95% CI)=1.03 (0.99-1.08), with similar findings for knee and multi-joint OA. We found similar magnitudes of associations for Hannum epigenetic age, PhenoAge, and GrimAge acceleration compared to Horvath epigenetic age acceleration. ConclusionsEpigenetic age acceleration as measured by various well-validated epigenetic clocks based on DNA methylation was not associated with increased risk of knee, hand, or multi-joint OA independent of chronological age.

Epigenetic Age Acceleration and Chronological Age: Associations With Cognitive Performance in Daily Life.

DNA methylation-derived epigenetic clocks offer the opportunity to examine aspects of age acceleration (ie, the difference between an individual's biological age and chronological age), which vary among individuals and may better account for age-related changes in cognitive function than chronological age. Leveraging existing ambulatory cognitive assessments in daily life from a genetically diverse sample of 142 adults in midlife, we examined associations between 5 measures of epigenetic age acceleration and performance on tasks of processing speed and working memory. Covarying for chronological age, we used multilevel models to examine associations of epigenetic age acceleration (Horvath 1, Horvath 2, Hannum, PhenoAge, and GrimAge clocks) with both average level and variability of cognitive performance. Positive age acceleration (ie, epigenetic age greater than chronological age) was associated with poorer mean processing speed (Horvath 1 and 2) and working memory (GrimAge). Higher chronological age was also associated with poorer mean processing speed and working memory performance. Further, positive age acceleration was generally associated with greater intraindividual variability in working memory and processing speed tasks, whereas being chronologically older was associated with less intraindividual variability. Although further work is needed, our results indicate age acceleration effects have comparable or greater size as those for chronological age differences, suggesting that epigenetic age acceleration may account for additional risk and interindividual variation in cognitive performance above chronological age.

Associations between medium- and long-term exposure to air temperature and epigenetic age acceleration

Climate change poses a serious threat to human health worldwide, while aging populations increase. However, no study has ever investigated the effects of air temperature on epigenetic age acceleration. This study involved 1,725 and 1,877 participants from the population-based KORA F4 (2006–2008) and follow-up FF4 (2013–2014) studies, respectively, conducted in Augsburg, Germany. The difference between epigenetic age and chronological age was referred to as epigenetic age acceleration and reflected by Horvath’s epigenetic age acceleration (HorvathAA), Hannum’s epigenetic age acceleration (HannumAA), PhenoAge acceleration (PhenoAA), GrimAge acceleration (GrimAA), and Epigenetic Skin and Blood Age acceleration (SkinBloodAA). Daily air temperature was estimated using hybrid spatiotemporal regression-based models. To explore the medium- and long-term effects of air temperature modeled in time and space on epigenetic age acceleration, we applied generalized estimating equations (GEE) with distributed lag non-linear models, and GEE, respectively. We found that high temperature exposure based on the 8-week moving average air temperature (97.5th percentile of temperature compared to median temperature) was associated with increased HorvathAA, HannumAA, GrimAA, and SkinBloodAA: 1.83 (95% CI: 0.29–3.37), 11.71 (95% CI: 8.91–14.50), 2.26 (95% CI: 1.03–3.50), and 5.02 (95% CI: 3.42–6.63) years, respectively. Additionally, we found consistent results with high temperature exposure based on the 4-week moving average air temperature was associated with increased HannumAA, GrimAA, and SkinBloodAA: 9.18 (95% CI: 6.60–11.76), 1.78 (95% CI: 0.66–2.90), and 4.07 (95% CI: 2.56–5.57) years, respectively. For the spatial variation in annual average temperature, a 1 °C increase was associated with an increase in all five measures of epigenetic age acceleration (HorvathAA: 0.41 [95% CI: 0.24–0.57], HannumAA: 2.24 [95% CI: 1.95–2.53], PhenoAA: 0.32 [95% CI: 0.05–0.60], GrimAA: 0.24 [95%: 0.11–0.37], and SkinBloodAA: 1.17 [95% CI: 1.00–1.35] years). In conclusion, our results provide first evidence that medium- and long-term exposures to high air temperature affect increases in epigenetic age acceleration.

Epigenetic age acceleration mediates the association between smoking and diabetes-related outcomes

BackgroundSmoking 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 resultsIn 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.ConclusionsThis 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.

Persistent accelerated epigenetic ageing in a longitudinal cohort of vertically infected HIV-positive adolescents

We have previously shown accelerated ageing in adolescents perinatally infected with HIV (PHIV +), based on discrepancies between epigenetic and chronological age. The current study examines follow-up longitudinal patterns of epigenetic ageing and the association of epigenetic ageing with cognition as well as whole brain structure changes in PHIV + and healthy controls enrolled in the Cape Town Adolescent Antiretroviral Cohort Study (CTAAC). The Illumina EPIC array was used to generate blood DNA methylation data from 60 PHIV + adolescents and 36 age-matched controls aged 9–12 years old at baseline and again at a 36-month follow-up. Epigenetic clock software estimated two measures of epigenetic age acceleration: extrinsic epigenetic accelerated ageing (EEAA) and age acceleration difference (AAD) at both time points. At follow-up, each participant completed neuropsychological testing, structural magnetic resonance imaging, and diffusion tensor imaging. At follow-up, PHIV infection remains associated with increased EEAA and AAD. Accelerated epigenetic ageing remained positively associated with viral load and negatively associated with CD4 ratio. EEAA was positively associated with whole brain grey matter volume and alterations in whole brain white matter integrity. AAD and EEAA were not associated with cognitive function within the PHIV + group. Measures of epigenetic ageing, as detected in DNA methylation patterns, remain increased in PHIV + adolescents across a 36-month period. Associations between epigenetic ageing measures, viral biomarkers, and alterations in brain micro- and macrostructure also persist at 36-month follow-up. Further study should determine if epigenetic age acceleration is associated with cognitive functional changes due to brain alterations in later life.

Associations between prenatal phthalate exposure and childhood epigenetic age acceleration

Phthalates, a group of pervasive endocrine-disrupting chemicals found in plastics and personal care products, have been associated with a wide range of developmental and health outcomes. However, their impact on biomarkers of aging has not been characterized. We tested associations between prenatal exposure to 11 phthalate metabolites on epigenetic aging in children at birth, 7, 9, and 14 years of age. We hypothesized that prenatal phthalate exposure will be associated with epigenetic age acceleration measures at birth and in early childhood, with patterns dependent on sex and timing of DNAm measurement. Among 385 mother-child pairs from the CHAMACOS cohort, we measured DNAm at birth, 7, 9, and 14 years of age, and utilized adjusted linear regression to assess the association between prenatal phthalate exposure and Bohlin's Gestational Age Acceleration (GAA) at birth and Intrinsic Epigenetic Age Acceleration (IEAA) throughout childhood. Additionally, quantile g-computation was utilized to assess the effect of the phthalate mixture on GAA at birth and IEAA throughout childhood. We found a negative association between prenatal di (2-ethylhexyl) phthalate (DEHP) exposure and IEAA among males at age 7 (-0.62 years; 95% CI:-1.06 to -0.18), and a marginal negative association between the whole phthalate mixture and GAA among males at birth (-1.54 days, 95% CI: -2.79 to -0.28), while most other associations were nonsignificant. Our results suggest that prenatal exposure to certain phthalates is associated with epigenetic aging in children. Additionally, our findings suggest that the influence of prenatal exposures on epigenetic age may only manifest during specific periods of child development, and studies relying on DNAm measurements solely from cord blood or single time points may overlook potential relationships.

Appraising the Associations Between Systemic Iron Status and Epigenetic Clocks: A Genetic Correlation and Bidirectional Mendelian Randomization Study

BackgroundGenetic correlations (Rg) and bidirectional causal effects between systemic iron status and epigenetic clocks have not been fully investigated, although observational studies have suggested systemic iron status is associated with human aging. ObjectivesWe explored the genetic correlations and bidirectional causal effects between systemic iron status and epigenetic clocks. MethodsLeveraging large-scale genome-wide association study summary-level statistics for 4 systemic iron status biomarkers (ferritin, serum iron, transferrin, and transferrin saturation) (N = 48,972) and 4 measures for epigenetic age (GrimAge, PhenoAge, intrinsic epigenetic age acceleration (IEAA), and HannumAge) (N = 34,710), genetic correlations, and bidirectional causal effects were estimated between them mainly by applying linkage disequilibrium score (LDSC) regression, Mendelian randomization (MR), and MR based on Bayesian model averaging. The main analyses were conducted employing multiplicative random-effects inverse-variance weighted MR. MR-Egger, weighted median, weighted mode, and MR-PRESSO were performed as sensitivity analyses to support the robustness of causal effects. ResultsThe LDSC results illustrated Rg between serum iron and PhenoAge (Rg = 0.1971, P = 0.048) and between transferrin saturation and PhenoAge (Rg = 0.196, P = 0.0469). We found that increased ferritin and transferrin saturation significantly increased all 4 measures of epigenetic age acceleration (all P < 0.0125, β > 0). Each standard deviation genetically increases in serum iron only significantly associated with increased IEAA (β: 0.36; 95% CI: 0.16, 0.57; P = 6.01 × 10−4) and increased HannumAge acceleration (β: 0.32; 95% CI: 0.11, 0.52; P = 2.69 × 10−3). Evidence showed a suggestively significant causal effect of transferrin on epigenetic age acceleration (all 0.0125 <P < 0.05). Additionally, reverse MR study indicated no significant causal effect of epigenetic clocks on systemic iron status. ConclusionsAll 4 iron status biomarkers had a significant or suggestively significant causal effect on epigenetic clocks, whereas reverse MR studies did not.

Multi-omic underpinnings of epigenetic aging and human longevity

Biological aging is accompanied by increasing morbidity, mortality, and healthcare costs; however, its molecular mechanisms are poorly understood. Here, we use multi-omic methods to integrate genomic, transcriptomic, and metabolomic data and identify biological associations with four measures of epigenetic age acceleration and a human longevity phenotype comprising healthspan, lifespan, and exceptional longevity (multivariate longevity). Using transcriptomic imputation, fine-mapping, and conditional analysis, we identify 22 high confidence associations with epigenetic age acceleration and seven with multivariate longevity. FLOT1, KPNA4, and TMX2 are novel, high confidence genes associated with epigenetic age acceleration. In parallel, cis-instrument Mendelian randomization of the druggable genome associates TPMT and NHLRC1 with epigenetic aging, supporting transcriptomic imputation findings. Metabolomics Mendelian randomization identifies a negative effect of non-high-density lipoprotein cholesterol and associated lipoproteins on multivariate longevity, but not epigenetic age acceleration. Finally, cell-type enrichment analysis implicates immune cells and precursors in epigenetic age acceleration and, more modestly, multivariate longevity. Follow-up Mendelian randomization of immune cell traits suggests lymphocyte subpopulations and lymphocytic surface molecules affect multivariate longevity and epigenetic age acceleration. Our results highlight druggable targets and biological pathways involved in aging and facilitate multi-omic comparisons of epigenetic clocks and human longevity.

Issue highlights

Hans Asperger is best known for Asperger syndrome, but has been accused of knowingly referring patients to a Viennese children's home notorious for murdering disabled children during the Nazi occupation. Two of the 13 children he referred there died. Tatzer et al.1 assessed original documents and found no evidence that Asperger was aware of the ‘euthanasia’ programme when he referred them. Czech strongly criticises the paper and says Asperger must have known about the ‘euthanasia’ programme early on, because he worked with the doctor responsible for the murders.2 Gillberg shares his thoughts on Asperger and meeting his daughter.3 A review by de Boer et al.4 looks at parents' perspectives about making prenatal decisions regarding treatment for babies born at the limit of viability. It is accompanied by a perspective, where the parents of an infant born at 24 weeks of gestation share their experiences5 after an unexpected pregnancy was discovered at 18 weeks. They faced the risk of an extremely premature birth at 22 weeks and agreed with the physicians to initiate intensive care treatment if their infant was born in the grey zone. Poor sleep has been associated with poor physical and mental health, including increased risks of heart disease and type 2 diabetes and higher levels of symptoms of depression and anxiety. Balfour et al.6 looked at the parent-reported sleep trajectories of 1192 young Australians from 5 to 17 years of age and the subject's self-reported sleep problems. They found no relationships between these sleep-related reports and measures of epigenetic age acceleration at 17 years of age, after adjusting for depressive symptoms. Størksen et al.7 reviewed the literature on Internet-based interventions that aim to support the parents of young children aged 0–5 years. They found that more interventions focused on mental health than somatic health, with developmental disorders and obesity being the most frequently studied conditions in those respective categories. Several gaps were identified, such as the need for more research outside English-speaking countries. The authors suggest that program developers should consider using more audio-visual technology to avoid reinforcing social inequalities in access to healthcare. Holter comments on the findings.8 Researchers in many medical fields are increasingly reporting outcomes that are important to patients who have shared their lived experiences with their illnesses. Thivierge et al.9 explored the pulmonary outcomes that were important to parents after extremely preterm birth and created a list that could be considered by future respiratory outcome studies. These reflected outcomes during the infants' neonatal intensive care hospitalisation and after discharge. The 285 parents described numerous important pulmonary events, but the authors were interested to note that bronchopulmonary dysplasia was not on the list, despite being the main respiratory outcome investigated in neonatology. Figure 1: Alamy, Figure 2-5: Istockphoto

Effects of epigenetic age acceleration on kidney function: a Mendelian randomization study

BackgroundPrevious studies have reported cross-sectional associations between measures of epigenetic age acceleration (EAA) and kidney function phenotypes. However, the temporal and potentially causal relationships between these variables remain unclear. We conducted a bidirectional two-sample Mendelian randomization study of EAA and kidney function. Genetic instruments for EAA and estimate glomerular filtration rate (eGFR) were identified from previous genome-wide association study (GWAS) meta-analyses of European-ancestry participants. Causal effects of EAA on kidney function and kidney function on EAA were assessed through summary-based Mendelian randomization utilizing data from the CKDGen GWAS meta-analysis of log-transformed estimated glomerular filtration rate (log-eGFR; n = 5,67,460) and GWAS meta-analyses of EAA (n = 34,710). An allele score-based Mendelian randomization leveraging individual-level data from UK Biobank participants (n = 4,33,462) further examined the effects of EAA on kidney function.ResultsUsing summary-based Mendelian randomization, we found that each 5 year increase in intrinsic EAA (IEAA) and GrimAge acceleration (GrimAA) was associated with − 0.01 and − 0.02 unit decreases in log-eGFR, respectively (P = 0.02 and P = 0.09, respectively), findings which were strongly supported by allele-based Mendelian randomization study (both P < 0.001). Summary-based Mendelian randomization identified 24% increased odds of CKD with each 5-unit increase in IEAA (P = 0.05), with consistent findings observed in allele score-based analysis (P = 0.07). Reverse-direction Mendelian randomization identified potentially causal effects of decreased kidney function on HannumAge acceleration (HannumAA), GrimAA, and PhenoAge acceleration (PhenoAA), conferring 3.14, 1.99, and 2.88 year decreases in HanumAA, GrimAA, and PhenoAA, respectively (P = 0.003, 0.05, and 0.002, respectively) with each 1-unit increase in log-eGFR.ConclusionThis study supports bidirectional causal relationships between EAA and kidney function, pointing to potential prevention and therapeutic strategies.

Childhood sleep health and epigenetic age acceleration in late adolescence: Cross-sectional and longitudinal analyses.

Investigate if childhood measures of sleep health are associated with epigenetic age acceleration in late adolescence. Parent-reported sleep trajectories from age 5 to 17, self-reported sleep problems at age 17, and six measures of epigenetic age acceleration at age 17 were studied in 1192 young Australians from the Raine Study Gen2. There was no evidence for a relationship between the parent-reported sleep trajectories and epigenetic age acceleration (p ≥ 0.17). There was a positive cross-sectional relationship between self-reported sleep problem score and intrinsic epigenetic age acceleration at age 17 (b=0.14, p=0.04), which was attenuated after controlling for depressive symptom score at the same age (b=0.08, p=0.34). Follow-up analyses suggested this finding may represent greater overtiredness and intrinsic epigenetic age acceleration in adolescents with higher depressive symptoms. There was no evidence for a relationship between self- or parent-reported sleep health and epigenetic age acceleration in late adolescence after adjusting for depressive symptoms. Mental health should be considered as a potential confounding variable in future research on sleep and epigenetic age acceleration, particularly if subjective measures of sleep are used.

Abstract P304: Association of Epigenetic Age Acceleration With Cognition in the Bogalusa Heart Study

Background: Despite known associations of epigenetic age acceleration (EAA), or increased DNA methylation (DNAm)-based age relative to chronological age, with Alzheimer’s disease, few studies have investigated the relation of EAA with midlife cognitive function. We examined cross-sectional associations of EAA with cognition among the 1,252 middle-aged participants of the Bogalusa Heart Study 2013-2016 study visit. Methods: Whole-blood DNA methylation data was generated using the Illumina HumanMethylation450 BeadChip. Four EAA measures, including extrinsic EAA (EEAA), intrinsic EAA (IEAA), PhenoAA and GrimAA, were derived from the methylation data. Cognitive function was assessed by a standard battery of eight neurocognitive tests covering five cognition domains, and a global cognition score was calculated. Associations of EAA measures with cognitive function were assessed by 3 multivariable models sequentially adding (i) demographics (age, sex, race, education) and vocabulary; (ii) lifestyle behaviors (smoking, alcohol drinking, and depression), and (iii) clinical measures (blood pressure, lipids, body mass index, glycated hemoglobin, medication, and white blood cell count. Results: After Bonferroni correction (α=1.39E-3), PhenoAA and GrimAA were significantly associated with decreased processing speed (lower Digit coding test score) and decreased working memory (higher trail making test A score). GrimAA was also associated with lower global cognition score ( Table ). EEAA was associated with decreased processing speed (lower Digit coding test). After adjusting for lifestyle and clinical measures, such associations were slightly attenuated but remained at least nominally significant. IEAA was not associated with any cognitive test results. Conclusions: EAA measured by PhenoAA, GrimAA, and EEAA were significantly associated with decreased processing speed, working memory, and/or global cognition. The associations were independent of known cognitive decline risk factors.

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

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

Epigenetic clocks derived from western samples differentially reflect Taiwanese health outcomes.

Introduction: Several epigenetic clocks have been developed, with five measures of epigenetic age acceleration (EAA) especially receiving extensive investigations: HannumEAA, IEAA, PhenoEAA, GrimEAA, and DunedinPACE. These epigenetic clocks were mainly developed by individuals of European or Hispanic ancestry. It remains unclear whether they can reflect disease morbidity and physiological conditions in Asian populations. Methods: I here investigated five measures of EAA of 2,474 Taiwan Biobank participants with DNA methylation data. Using logistic regressions, I sequentially regressed various health outcomes on each of the five measures of EAA while adjusting for chronological age, sex, body mass index, the number of smoking pack-years, drinking status, regular exercise, educational attainment, and six cell-type proportions. Results: Except for IEAA, all measures of EAA reflected the obesity of Taiwanese (p < 4.0E-4). Diabetes was reflected by DunedinPACE (p = 5.4E-6) and GrimEAA (p = 5.8E-5). Moreover, DunedinPACE was associated with dyslipidemia, including hypertriglyceridemia (p = 1.1E-5), low high-density lipoprotein cholesterol (HDL-C) (p = 4.0E-5), and high triglyceride to HDL-C ratio (p = 1.6E-7). Discussion: This is one of the first studies to show that epigenetic clocks (developed by individuals of European or Hispanic ancestry) can reflect Taiwanese physiological conditions. DunedinPACE was associated with more Taiwanese health outcomes than the other four measures of EAA.

Epigenetic aging differences between Wichí and Criollos from Argentina: Insights from genomic history and ecology.

Epigenetic estimators based on DNA methylation levels have emerged as promising biomarkers of human aging. These estimators exhibit natural variations across human groups, but data about indigenous populations remain underrepresented in research. This study aims to investigate differences in epigenetic estimators between two distinct human populations, both residing in the Gran Chaco region of Argentina, the Native-American Wichí, and admixed Criollos who are descendants of intermarriages between Native Americans and the first European colonizers, using a population genetic approach. We analyzed 24 Wichí (mean age: 39.2 ± 12.9 yo) and 24 Criollos (mean age: 41.1 ± 14.0 yo) for DNA methylation levels using the Infinium MethylationEPIC (Illumina) to calculate 16 epigenetic estimators. Additionally, we examined genome-wide genetic variation using the HumanOmniExpress BeadChip (Illumina) to gain insights into the genetic history of these populations. Our results indicate that Native-American Wichí are epigenetically older compared to Criollos according to five epigenetic estimators. Analyses within the Criollos population reveal that global ancestry does not influence the differences observed, while local (chromosomal) ancestry shows positive associations between specific SNPs located in genomic regions over-represented by Native-American ancestry and measures of epigenetic age acceleration (AgeAccelHannum). Furthermore, we demonstrate that differences in population ecologies also contribute to observed epigenetic differences. Overall, our study suggests that while the genomic history may partially account for the observed epigenetic differences, non-genetic factors, such as lifestyle and ecological factors, play a substantial role in the variability of epigenetic estimators, thereby contributing to variations in human epigenetic aging.

Associations Between Epigenetic Age Acceleration and microRNA Expression Among U.S. Firefighters.

Epigenetic changes may be biomarkers of health. Epigenetic age acceleration (EAA), the discrepancy between epigenetic age measured via epigenetic clocks and chronological age, is associated with morbidity and mortality. However, the intersection of epigenetic clocks with microRNAs (miRNAs) and corresponding miRNA-based health implications have not been evaluated. We analyzed DNA methylation and miRNA profiles from blood sampled among 332 individuals enrolled across 2 U.S.-based firefighter occupational studies (2015-2018 and 2018-2020). We considered 7 measures of EAA in leukocytes (PhenoAge, GrimAge, Horvath, skin-blood, and Hannum epigenetic clocks, and extrinsic and intrinsic epigenetic age acceleration). We identified miRNAs associated with EAA using individual linear regression models, adjusted for sex, race/ethnicity, chronological age, and cell type estimates, and investigated downstream effects of associated miRNAs with miRNA enrichment analyses and genomic annotations. On average, participants were 38 years old, 88% male, and 75% non-Hispanic white. We identified 183 of 798 miRNAs associated with EAA (FDR q < 0.05); 126 with PhenoAge, 59 with GrimAge, 1 with Horvath, and 1 with the skin-blood clock. Among miRNAs associated with Horvath and GrimAge, there were 61 significantly enriched disease annotations including age-related metabolic and cardiovascular conditions and several cancers. Enriched pathways included those related to proteins and protein modification. We identified miRNAs associated with EAA of multiple epigenetic clocks. PhenoAge had more associations with individual miRNAs, but GrimAge and Horvath had greater implications for miRNA-associated pathways. Understanding the relationship between these epigenetic markers could contribute to our understanding of the molecular underpinnings of aging and aging-related diseases.

Receptive Language Abilities for Females Exposed to Early Life Adversity: Modification by Epigenetic Age Acceleration at Midlife in a 30-Year Prospective Cohort Study.

Deviations from normative trajectories of receptive language abilities following early life adversity (ELA) may indicate an elevated risk for advanced cognitive aging and related morbidities. Accelerated epigenetic aging at midlife may further identify those at greatest risk for advanced cognitive aging following ELA. We examined whether accelerations in epigenetic aging at midlife can identify those individuals who demonstrated the greatest change in receptive language abilities following ELA. Data were drawn from the Female Growth and Development Study (n=86), a 30-year prospective cohort study of females exposed to substantiated child sexual abuse (CSA), a severe ELA, and a non-CSA comparison condition. The Peabody Picture Vocabulary Test-Revised (PPVT-R) measured receptive language abilities on 6 occasions from childhood to mid-life. Interindividual differences in PPVT-R trajectories were examined in relation to CSA exposure and across 5 independent measures of epigenetic age acceleration derived from first (Horvath DNAmAge, Hannum DNAmAge) and second (GrimAge, PhenoAge, Dunedin Pace of Aging) generation epigenetic clocks. Quadratic growth models revealed that PPVT-R scores were significantly lower at age 25 for females exposed to CSA. Specifically, CSA exposed females had lower intercepts when GrimAge was accelerated and a smaller quadratic trend when PhenoAge was accelerated. ELA is associated with significant differences in development of receptive language abilities with the most pronounced differences observed for females with accelerated epigenetic ages at mid-life. These findings suggest that epigenetic age acceleration could serve as an indicator of differences in cognitive aging and portend to later adulthood cognitive functioning.