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Background: The risks of obesity and epigenetic age acceleration (EAA) have drawn widespread attention. Lipid accumulation product (LAP) is a simple and reliable indicator of obesity; however, the relationship between LAP and EAA remains unclear. Methods: Data from the National Health and Nutrition Examination Survey (NHANES) from 1999 to 2002 were used. The EAA was assessed using a self-administered questionnaire in the database. LAP was calculated based on triglycerides and waist circumference. The association between LAP and EAA was analyzed using logistic regression models, subgroup analysis, and smooth curve fitting. Results: A total of 1796 participants were included in the study, of whom 1055 had EAA. After adjusting for relevant covariates, participants with EAA generally had higher LAP levels than those without EAA (258.1 vs. 244.6). Logistic regression analysis showed that individuals in the highest LAP quartile (Q4) were more likely to have EAA than those in the lowest quartile (Q1) (OR = 1.77; 95% CI 1.31–2.39; P < 0.001). The area under the curve of the adjusted logistic regression analysis was 0.706. Conclusion: This research indicates that elevated LAP levels are independently linked to an increased risk of EAA, and early intervention to reduce high LAP levels is necessary to mitigate the progression of EAA. [ABSTRACT FROM AUTHOR]

Objectives Loneliness is a pressing public health concern, but the mechanisms by which it leads to declining physical health are uncertain. Prior work has begun to explore epigenetic pathways, with some evidence suggesting a link between loneliness and DNA methylation, though it is unclear whether epigenetic variation can help explain loneliness–health associations. Methods Associations between loneliness and epigenetic age acceleration (EAA) were estimated, as well as the degree to which EAA mediated and moderated the association between loneliness and the development of chronic physical health conditions (multimorbidity) in older adulthood. The sample consisted of Health and Retirement Study participants who provided blood draws and consented to methylation profiling (n  = 4,018). Results Baseline loneliness was associated with greater EAA in the GrimAge measure net of demographic and behavioral covariates (β = 0.07, p  = .003). Loneliness and GrimAge each predicted increasing condition counts, but there was no evidence of an interactive effect. The association between loneliness and increasing condition counts was, however, significantly mediated by GrimAge (indirect path β = 0.020, p  = .003). Discussion These results suggest that the impact of loneliness on multimorbidity may, in part, operate through DNA methylation. The specific intermediary, physiological mechanisms that are involved will require further research, but EAA measures like GrimAge are promising in helping to understand the health impacts of loneliness. [ABSTRACT FROM AUTHOR]

STUDY QUESTION Is there an association between male or female epigenetic age acceleration (EAA) or deceleration (EAD) and fecundability? SUMMARY ANSWER We do not find compelling evidence of an association between EAA or EAD and fecundability. WHAT IS KNOWN ALREADY Prior research has shown that female accelerated epigenetic aging is associated with unfavorable clinical fecundity outcomes and use of in vitro fertilization, and that epigenetic aging in sperm cells is associated with unfavorable sperm parameters. Studies of epigenetic aging and fecundability among individuals who conceive naturally are lacking. STUDY DESIGN, SIZE, DURATION This study is based on the Norwegian Mother, Father and Child Cohort Study (MoBa), a population-based pregnancy cohort which recruited pregnant couples between 1999 and 2008. We used data from 1657 couples (women and men) with planned naturally conceived pregnancies and available blood samples. PARTICIPANTS/MATERIALS, SETTING, METHODS Methylation levels were measured in DNA from blood samples taken recruitment (at ∼18 gestational weeks) from pregnant women and their partners using the Illumina Methylation EPIC Array. To obtain a measure of EAA/EAD, we performed a linear regression of each of seven different established epigenetic biomarkers (DNAmAge by Horvath, DNAmAge by Hannum et al. , PhenoAge by Levine et al. , DunedinPoAm by Belsky et al. , DunedinPACE by Belsky et al. , DNAmTL by Lu et al. , and GrimAge by Lu et al.) against chronological age. We fitted proportional probability regression models to obtain fecundability ratios (FRs) for each standard deviation increase in epigenetic aging, and obtained crude and adjusted (for body mass index, smoking, and education level) estimates. Results were evaluated at a false discovery rate (FDR) of 5%. We evaluated all models for non-linear associations using categories of epigenetic age where appropriate. MAIN RESULTS AND THE ROLE OF CHANCE Although the DunedinPACE clock in males demonstrated slightly increasing fecundability with increasing EAA (adjusted FR 1.05 per one standard deviation increase in EAA, 95% CI 1.00–1.10), this was not robust when evaluated at an FDR of 5%. We found evidence of non-linearity between biological aging and fecundability in two models in females and three models in males, but non-linear associations were weak and conflicting. LIMITATIONS, REASONS FOR CAUTION As MoBa is a pregnancy cohort, our findings may not be generalizable to all couples attempting conception. Fecundability is a couple-level measure, and any impacts of epigenetic aging in each partner may be obscured by effects of the other partner. WIDER IMPLICATIONS OF THE FINDINGS Our findings contrast with those of prior studies, which have indicated an association between EAA and unfavorable clinical fertility outcomes in populations using fertility treatments, possibly due to less important effects of epigenetic aging among couples who conceive naturally. More research is needed on the association between blood-based EAA and clinical fertility parameters in both sexes. STUDY FUNDING/COMPETING INTEREST(S) The study was supported by the Research Council of Norway through its Medical Student Research Program funding scheme (project number 271555/F20), its Centres of Excellence funding scheme (project number 262700), and a grant from the Women's Health Program (320656). Co-funding was also received from the Strategic Research Council (SRC), FLUX consortium, decision numbers 345130 and 345131; the National Institute on Aging (R01AG075208); grants to the Max Planck—University of Helsinki Center from the Max Planck Society (decision number 5714240218), Jane and Aatos Erkko Foundation, Faculty of Social Sciences at the University of Helsinki, and Cities of Helsinki, Vantaa, and Espoo; and the European Research Council; and the European Research Council (ERC Synergy, BIOSFER, grant number 101071773, and the Horizon 2020 research and innovation program, grant number 947684). The authors declare no conflicts of interest. TRIAL REGISTRATION NUMBER N/A. [ABSTRACT FROM AUTHOR]

Background: Pulmonary arterial hypertension (PAH) is a relatively rare but severe disease with a poor prognosis. Pulmonary embolism (PE) is a serious condition that can cause sudden death. Epigenetic age acceleration (EAA) is a robust indicator derived from the DNA methylation-based epigenetic clock, which can predict the extent of aging. It has been proved that the epigenetic clock and EAA are associated with many cardiovascular diseases, while their associations with PAH and PE remain inconclusive. Our study aims to investigate the associations among these factors. Method: By harnessing summary-level data from large-scale genome-wide association studies (GWAS), we designed a two-sample bidirectional Mendelian randomization (MR) analysis to assess the causal associations between measures of three epigenetic clocks, including GrimAge acceleration (n = 34,467), Hannum Age acceleration (n = 34,449) and PhenoAge acceleration (n = 34,463) and PAH (including 125 cases and 162,837 controls), as well as PE (including 3940 cases and 480,658 controls). The inverse variance-weighted (IVW) method was used as the primary method for MR analysis. Other methods, such as MR egger and weighted mode, served as complements to the IVW approach, were also applied in the analyses. Then, the MR pleiotropy test and MR-PRESSO test, which are effective tools for quality control of MR analysis, were subsequently used to ensure the accuracy of the study. Results: The forward MR analysis indicated that all three epigenetic clocks had no significant effects on PAH or PE. The reverse analysis indicated that the onset and progression of PAH and PE had insignificant effects on three epigenetic clocks. The results of the quality control assessment confirmed that our findings were reliable. Conclusion: Our two-sample bidirectional MR analysis suggested that there is no significant association between epigenetic clocks and these two pulmonary vascular diseases. [ABSTRACT FROM AUTHOR]

Background: The gut microbiota is closely related to aging, but the genetic relationship between gut microbiota and aging has not been well investigated. The aim of the study was to explore the association of microbiota with epigenetic age acceleration (EAA) using the Mendelian randomization. Method: The independent genetic instruments of gut microbiota were obtained from MiBioGen consortium and the Dutch Microbiome Project. EAA data were derived from genome-wide association study. To assess the causal relationship between gut microbiota and EAA, we applied four different methods of Mendelian Randomization (MR) analysis: the inverse variance weighted method (IVW), the MR-Egger regression, the weighted median analysis (WMA), and the weighted mode. Furthermore, sensitivity analyses were conducted to evaluate heterogeneity and horizontal pleiotropy. Results: We identified potential causal associations between 12 bacterial taxa and EAA (PIVW and PWMA < 0.05). Among them, species Holdemania_unclassified (OR: 1.31, 95% CI: 1.13–1.52, P = 0.0004) retained a strong positive association with GrimAge acceleration. Family Acidaminococcaceae (OR: 0.64, 95% CI: 0.44–0.93, P = 0.019) and family Clostridiaceae1 (OR: 0.69, 95% CI: 0.49–0.97 P = 0.031) were negative association with GrimAge acceleration. Reverse MR analyses indicated that EAA was associated with 6 bacterial taxa in IVW and WMA. Among them, a strong inverse association was found between Phenoage acceleration and genus Turicibacter (OR: 0.928, 95%CI: 0.888–0.971, PIVW and PWMA < 0.001). Conclusion: Our study implicates the potential causal effects of specific microbiota on EAA, potentially providing novel insights into the prevention aging through specific gut microbiota. [ABSTRACT FROM AUTHOR]

The causative mechanisms underlying the genetic relationships of neurodegenerative diseases with epigenetic aging and human longevity remain obscure. We aimed to detect causal associations and shared genetic etiology of neurodegenerative diseases with epigenetic aging and human longevity. We obtained large‐scale genome‐wide association study summary statistics data for four measures of epigenetic age (GrimAge, PhenoAge, IEAA, and HannumAge) (N = 34,710), multivariate longevity (healthspan, lifespan, and exceptional longevity) (N = 1,349,462), and for multiple neurodegenerative diseases (N = 6618–482,730), including Lewy body dementia, Alzheimer's disease (AD), Parkinson's disease, amyotrophic lateral sclerosis, and multiple sclerosis. Main analyses were conducted using multiplicative random effects inverse‐variance weighted Mendelian randomization (MR), and conditional/conjunctional false discovery rate (cond/conjFDR) approach. Shared genomic loci were functionally characterized to gain biological understanding. Evidence showed that AD patients had 0.309 year less in exceptional longevity (IVW beta = −0.309, 95% CI: −0.38 to −0.24, p = 1.51E‐19). We also observed suggestively significant causal evidence between AD and GrimAge age acceleration (IVW beta = −0.10, 95% CI: −0.188 to −0.013, p = 0.02). Following the discovery of polygenic overlap, we identified rs78143120 as shared genomic locus between AD and GrimAge age acceleration, and rs12691088 between AD and exceptional longevity. Among these loci, rs78143120 was novel for AD. In conclusion, we observed that only AD had causal effects on epigenetic aging and human longevity, while other neurodegenerative diseases did not. The genetic overlap between them, with mixed effect directions, suggested complex shared genetic etiology and molecular mechanisms. [ABSTRACT FROM AUTHOR]

• Epigenetic clocks leverage artificial intelligence to predict biological age by analyzing specific age-related CpG sites • An overview of classic epigenetic clocks is provided • Epigenetic clocks help identify aging risk factors and evaluate anti-aging interventions • The potential of epigenetic clocks to predict the onset of aging-related diseases is explored • The current limitations of epigenetic clocks are discussed, along with prospects for future development The process of aging is a notable risk factor for numerous age-related illnesses. Hence, a reliable technique for evaluating biological age or the pace of aging is crucial for understanding the aging process and its influence on the progression of disease. Epigenetic alterations are recognized as a prominent biomarker of aging, and epigenetic clocks formulated on this basis have been shown to provide precise estimations of chronological age. Extensive research has validated the effectiveness of epigenetic clocks in determining aging rates, identifying risk factors for aging, evaluating the impact of anti-aging interventions, and predicting the emergence of age-related diseases. This review provides a detailed overview of the theoretical principles underlying the development of epigenetic clocks and their utility in aging research. Furthermore, it explores the existing obstacles and possibilities linked to epigenetic clocks and proposes potential avenues for future studies in this field. [ABSTRACT FROM AUTHOR]

Abstract Background The risks of obesity and epigenetic age acceleration (EAA) have drawn widespread attention. Lipid accumulation product (LAP) is a simple and reliable indicator of obesity; however, the relationship between LAP and EAA remains unclear. Methods Data from the National Health and Nutrition Examination Survey (NHANES) from 1999 to 2002 were used. The EAA was assessed using a self-administered questionnaire in the database. LAP was calculated based on triglycerides and waist circumference. The association between LAP and EAA was analyzed using logistic regression models, subgroup analysis, and smooth curve fitting. Results A total of 1796 participants were included in the study, of whom 1055 had EAA. After adjusting for relevant covariates, participants with EAA generally had higher LAP levels than those without EAA (258.1 vs. 244.6). Logistic regression analysis showed that individuals in the highest LAP quartile (Q4) were more likely to have EAA than those in the lowest quartile (Q1) (OR = 1.77; 95% CI 1.31–2.39; P

Abstract Background Pulmonary arterial hypertension (PAH) is a relatively rare but severe disease with a poor prognosis. Pulmonary embolism (PE) is a serious condition that can cause sudden death. Epigenetic age acceleration (EAA) is a robust indicator derived from the DNA methylation-based epigenetic clock, which can predict the extent of aging. It has been proved that the epigenetic clock and EAA are associated with many cardiovascular diseases, while their associations with PAH and PE remain inconclusive. Our study aims to investigate the associations among these factors. Method By harnessing summary-level data from large-scale genome-wide association studies (GWAS), we designed a two-sample bidirectional Mendelian randomization (MR) analysis to assess the causal associations between measures of three epigenetic clocks, including GrimAge acceleration (n = 34,467), Hannum Age acceleration (n = 34,449) and PhenoAge acceleration (n = 34,463) and PAH (including 125 cases and 162,837 controls), as well as PE (including 3940 cases and 480,658 controls). The inverse variance-weighted (IVW) method was used as the primary method for MR analysis. Other methods, such as MR egger and weighted mode, served as complements to the IVW approach, were also applied in the analyses. Then, the MR pleiotropy test and MR-PRESSO test, which are effective tools for quality control of MR analysis, were subsequently used to ensure the accuracy of the study. Results The forward MR analysis indicated that all three epigenetic clocks had no significant effects on PAH or PE. The reverse analysis indicated that the onset and progression of PAH and PE had insignificant effects on three epigenetic clocks. The results of the quality control assessment confirmed that our findings were reliable. Conclusion Our two-sample bidirectional MR analysis suggested that there is no significant association between epigenetic clocks and these two pulmonary vascular diseases.

Abstract Background Epigenetic age accelerations (EAAs) are a promising new avenue of research, yet their investigation in subacute thyroiditis (SAT) remains scarce. Our study endeavors to fill this void by exploring the potential causal association between EAAs and SAT. Methods Our study utilized publicly available genome-wide association study (GWAS) data of European ancestry to conduct a bidirectional Mendelian randomization (MR) study. Five MR methods were employed to measure causal association between EAAs and SAT multiple analyses were utilized to perform quality control. Results Our study evaluated causal association between SAT and four EAAs, included GrimAge acceleration (GrimAA), Hannum age acceleration (HannumAA), PhenoAge acceleration (PhenoAA), intrinsic epigenetic age acceleration (IEAA). Results showed that there is a significant causal association between PhenoAA and SAT (OR 1.109, 95% CI 1.000–1.228, p = 0.049, by IVW method). On the contrary, SAT was associated with IEAA (OR 0.933, 95% CI 0.884–0.984, p = 0.011, by IVW method; OR 0.938, 95% CI 0.881–0.998, p = 0.043, by weighted median method). Leave-one-out sensitivity analysis, heterogeneity test, pleiotropy test, and MR-PRESSO analysis provide good quality control. Conclusion The bidirectional MR analysis concluded that an increase in PhenoAA was correlated with a higher risk of SAT, indicating a potential causal relationship between PhenoAA and risk of SAT. Conversely, SAT was found to be closely associated with IEAA, suggesting that SAT may accelerate the aging process. Slowing down biological aging has emerged as a new research direction in curbing SAT.

Abstract Whether differences in lifestyle between co-twins are reflected in differences in their internal or external exposome profiles remains largely underexplored. We therefore investigated whether within-pair differences in lifestyle were associated with within-pair differences in exposome profiles across four domains: the external exposome, proteome, metabolome and epigenetic age acceleration (EAA). For each domain, we assessed the similarity of co-twin profiles using Gaussian similarities in up to 257 young adult same-sex twin pairs (54% monozygotic). We additionally tested whether similarity in one domain translated into greater similarity in another. Results suggest that a lower degree of similarity in co-twins' exposome profiles was associated with greater differences in their behavior and substance use. The strongest association was identified between excessive drinking behavior and the external exposome. Overall, our study demonstrates how social behavior and especially substance use are connected to the internal and external exposomes, while controlling for familial confounders.

Abstract Background Human aging and white blood cell (WBC) count are complex traits influenced by multiple genetic factors. Predictors of chronological age have been developed using epigenetic clocks. However, the bidirectional causal effects between epigenetic clocks and WBC count have not been fully examined. Methods This study employed Mendelian randomization (MR) to analyze summary statistics from four epigenetic clocks involving 34,710 participants, alongside data from the Blood Cell Consortium encompassing 563,946 individuals. We primarily explored bidirectional causal relationships using the random-effects inverse-variance weighted method, supplemented by additional MR methods for comprehensive analysis. Additionally, multivariate MR was applied to investigate independent effects of WBC count on epigenetic age acceleration. Results In the two-sample univariate MR (UVMR) analysis, we observed that a decrease in lymphocyte count markedly accelerated aging according to the PhenoAge, GrimAge, and HannumAge metrics (all P

Abstract Introduction Walking stands as the most prevalent physical activity in the daily lives of individuals and is closely associated with physical functioning and the aging process. Nonetheless, the precise cause-and-effect connection between walking and aging remains unexplored. The epigenetic clock emerges as the most promising biological indicator of aging, capable of mirroring the biological age of the human body and facilitating an investigation into the association between walking and aging. Our primary objective is to investigate the causal impact of walking with epigenetic age acceleration (EAA). Methods We conducted a two-sample two-way Mendelian randomization (MR) study to investigate the causal relationship between walking and EAA. Walking and Leisure sedentary behavior data were sourced from UK Biobank, while EAA data were gathered from a total of 28 cohorts. The MR analysis was carried out using several methods, including the inverse variance weighted (IVW), weighted median, MR-Egger, and robust adjusted profile score (RAPS). To ensure the robustness of our findings, we conducted sensitivity analyses, which involved the MR-Egger intercept test, Cochran’s Q test, and MR-PRESSO, to account for and mitigate potential pleiotropy. Results The IVW MR results indicate a significant impact of usual walking pace on GrimAge (BETA = − 1.84, 95% CI (− 2.94, − 0.75)), PhenoAge (BETA = − 1.57, 95% CI (− 3.05, − 0.08)), Horvath (BETA = − 1.09 (− 2.14, − 0.04)), and Hannum (BETA = − 1.63, 95% CI (− 2.70, − 0.56)). Usual walking pace is significantly associated with a delay in epigenetic aging acceleration (EAA) (P 0.05). Conclusion Our evidence demonstrates that a higher usual walking pace is associated with a deceleration of the acceleration of all four classical epigenetic clocks acceleration.

Abstract Background Healthy sleep is vital for maintaining optimal mental and physical health. Accumulating evidence suggests that sleep loss and disturbances play a significant role in the biological aging process, early onset of disease, and reduced lifespan. While numerous studies have explored the association between biological aging and its drivers, only a few studies have examined its relationship with sleep quality. In this study, we investigated the associations between sleep quality and epigenetic age acceleration using whole blood samples from a cohort of 692 Korean adults. Sleep quality of each participant was assessed using the validated Pittsburgh Sleep Quality Index (PSQI), which encompassed seven domains: subjective sleep quality, sleep latency, sleep duration, habitual sleep efficiency, sleep disturbance, use of sleep medication, and daytime dysfunction. Four epigenetic age accelerations (HorvathAgeAccel, HannumAgeAccel, PhenoAgeAccel, and GrimAgeAccel) and the pace of aging, DunedinPACE, were investigated for epigenetic aging estimates. Results Among the 692 participants (good sleepers [n = 441, 63.7%]; poor sleepers [n = 251, 36.3%]), DunedinPACE was positively correlated with PSQI scores in poor sleepers ( $$\gamma$$ γ =0.18, p

Abstract Background The epigenetic-age acceleration (EAA) represents the difference between chronological age and epigenetic age, reflecting accelerated biological aging. Observational studies suggested that oral disorders may impact DNA methylation patterns and aging, but their causal relationship remains largely unexplored. This study aimed to investigate potential causal associations between dental traits and EAA, as well as to identify possible mediators. Methods Using summary statistics of genome-wide association studies of predominantly European ancestry, we conducted univariable and multivariable Mendelian randomization (MR) to estimate the overall and independent effects of ten dental traits (dentures, bleeding gums, painful gums, loose teeth, toothache, ulcers, periodontitis, number of teeth, and two measures of caries) on four EAA subtypes (GrimAge acceleration [GrimAA], PhenoAge acceleration [PhenoAA], HannumAge acceleration [HannumAA] and intrinsic EAA [IEAA]), and used two-step Mendelian randomization to evaluate twelve potential mediators of the associations. Comprehensive sensitivity analyses were used to verity the robustness, heterogeneity, and pleiotropy. Results Univariable inverse variance weighted MR analyses revealed a causal effect of dentures on greater GrimAA (β: 2.47, 95% CI: 0.93–4.01, p = 0.002), PhenoAA (β: 3.00, 95% CI: 1.15–4.85, p = 0.001), and HannumAA (β: 1.96, 95% CI: 0.58–3.33, p = 0.005). In multivariable MR, the associations remained significant after adjusting for periodontitis, caries, number of teeth and bleeding gums. Three out of 12 aging risk factors were identified as mediators of the association between dentures and EAA, including body mass index, body fat percentage, and waist circumference. No evidence for reverse causality and pleiotropy were detected (p > 0.05). Conclusions Our findings supported the causal effects of genetic liability for denture wearing on epigenetic aging, with partial mediation by obesity. More attention should be paid to the obesity-monitoring and management for slowing EAA among denture wearers.

Background: Epigenetic age accelerations (EAAs) are a promising new avenue of research, yet their investigation in subacute thyroiditis (SAT) remains scarce. Our study endeavors to fill this void by exploring the potential causal association between EAAs and SAT. Methods: Our study utilized publicly available genome-wide association study (GWAS) data of European ancestry to conduct a bidirectional Mendelian randomization (MR) study. Five MR methods were employed to measure causal association between EAAs and SAT multiple analyses were utilized to perform quality control. Results: Our study evaluated causal association between SAT and four EAAs, included GrimAge acceleration (GrimAA), Hannum age acceleration (HannumAA), PhenoAge acceleration (PhenoAA), intrinsic epigenetic age acceleration (IEAA). Results showed that there is a significant causal association between PhenoAA and SAT (OR 1.109, 95% CI 1.000–1.228, p = 0.049, by IVW method). On the contrary, SAT was associated with IEAA (OR 0.933, 95% CI 0.884–0.984, p = 0.011, by IVW method; OR 0.938, 95% CI 0.881–0.998, p = 0.043, by weighted median method). Leave-one-out sensitivity analysis, heterogeneity test, pleiotropy test, and MR-PRESSO analysis provide good quality control. Conclusion: The bidirectional MR analysis concluded that an increase in PhenoAA was correlated with a higher risk of SAT, indicating a potential causal relationship between PhenoAA and risk of SAT. Conversely, SAT was found to be closely associated with IEAA, suggesting that SAT may accelerate the aging process. Slowing down biological aging has emerged as a new research direction in curbing SAT. [ABSTRACT FROM AUTHOR]

Whether differences in lifestyle between co-twins are reflected in differences in their internal or external exposome profiles remains largely underexplored. We therefore investigated whether within-pair differences in lifestyle were associated with within-pair differences in exposome profiles across four domains: the external exposome, proteome, metabolome and epigenetic age acceleration (EAA). For each domain, we assessed the similarity of co-twin profiles using Gaussian similarities in up to 257 young adult same-sex twin pairs (54% monozygotic). We additionally tested whether similarity in one domain translated into greater similarity in another. Results suggest that a lower degree of similarity in co-twins' exposome profiles was associated with greater differences in their behavior and substance use. The strongest association was identified between excessive drinking behavior and the external exposome. Overall, our study demonstrates how social behavior and especially substance use are connected to the internal and external exposomes, while controlling for familial confounders. [ABSTRACT FROM AUTHOR]

Background: Human aging and white blood cell (WBC) count are complex traits influenced by multiple genetic factors. Predictors of chronological age have been developed using epigenetic clocks. However, the bidirectional causal effects between epigenetic clocks and WBC count have not been fully examined. Methods: This study employed Mendelian randomization (MR) to analyze summary statistics from four epigenetic clocks involving 34,710 participants, alongside data from the Blood Cell Consortium encompassing 563,946 individuals. We primarily explored bidirectional causal relationships using the random-effects inverse-variance weighted method, supplemented by additional MR methods for comprehensive analysis. Additionally, multivariate MR was applied to investigate independent effects of WBC count on epigenetic age acceleration. Results: In the two-sample univariate MR (UVMR) analysis, we observed that a decrease in lymphocyte count markedly accelerated aging according to the PhenoAge, GrimAge, and HannumAge metrics (all P < 0.01, β < 0), though it did not affect Intrinsic Epigenetic Age Acceleration (IEAA). Conversely, an increase in neutrophil count significantly elevated PhenoAge levels (β: 0.38; 95% CI 0.14, 0.61; P = 1.65E−03 < 0.01). Reverse MR revealed no significant causal impacts of epigenetic clocks on overall WBC counts. Furthermore, in multivariate MR, the impact of lymphocyte counts on epigenetic aging metrics remained statistically significant. We also identified a marked causal association between neutrophil counts and PhenoAge, GrimAge, and HannumAge, with respective results showing strong associations (PhenoAge β: 0.78; 95% CI 0.47, 1.09; P = 8.26E−07; GrimAge β: 0.55; 95% CI 0.31, 0.79; P = 5.50E−06; HannumAge β: 0.42; 95% CI 0.18, 0.67; P = 6.30E−04). Likewise, eosinophil cell count demonstrated significant association with HannumAge (β: 0.33; 95% CI 0.13, 0.53; P = 1.43E−03 < 0.01). Conclusion: These findings demonstrated that within WBCs, lymphocyte and neutrophil counts exert irreversible and independent causal effects on the acceleration of PhenoAge, GrimAge, and HannumAge. Our findings highlight the critical role of WBCs in influencing epigenetic clocks and underscore the importance of considering immune parameters when interpreting epigenetic age. [ABSTRACT FROM AUTHOR]

COVID-19 has been contained; however, the side effects associated with its infection continue to be a challenge for public health, particularly for older adults. On the other hand, epigenetic status contributes to the inter-individual health status and is associated with COVID-19 severity. Nevertheless, current studies focus only on severe COVID-19. Considering that most of the worldwide population developed mild COVID-19 infection. In the present exploratory study, we aim to analyze the association of mild COVID-19 with epigenetic ages (HorvathAge, HannumAge, GrimAge, PhenoAge, SkinAge, and DNAmTL) and clinical variables obtained from a Mexican cohort of older adults. We found that all epigenetic ages significantly differ from the chronological age, but only GrimAge is elevated. Additionally, both the intrinsic epigenetic age acceleration (IEAA) and the extrinsic epigenetic age acceleration (EEAA) are accelerated in all patients. Moreover, we found that immunological estimators and DNA damage were associated with PhenoAge, SkinBloodHorvathAge, and HorvathAge, suggesting that the effects of mild COVID-19 on the epigenetic clocks are mainly associated with inflammation and immunology changes. In conclusion, our results show that the effects of mild COVID-19 on the epigenetic clock are mainly associated with the immune system and an increase in GrimAge, IEAA, and EEAA. [ABSTRACT FROM AUTHOR]

Introduction: Walking stands as the most prevalent physical activity in the daily lives of individuals and is closely associated with physical functioning and the aging process. Nonetheless, the precise cause-and-effect connection between walking and aging remains unexplored. The epigenetic clock emerges as the most promising biological indicator of aging, capable of mirroring the biological age of the human body and facilitating an investigation into the association between walking and aging. Our primary objective is to investigate the causal impact of walking with epigenetic age acceleration (EAA). Methods: We conducted a two-sample two-way Mendelian randomization (MR) study to investigate the causal relationship between walking and EAA. Walking and Leisure sedentary behavior data were sourced from UK Biobank, while EAA data were gathered from a total of 28 cohorts. The MR analysis was carried out using several methods, including the inverse variance weighted (IVW), weighted median, MR-Egger, and robust adjusted profile score (RAPS). To ensure the robustness of our findings, we conducted sensitivity analyses, which involved the MR-Egger intercept test, Cochran's Q test, and MR-PRESSO, to account for and mitigate potential pleiotropy. Results: The IVW MR results indicate a significant impact of usual walking pace on GrimAge (BETA = − 1.84, 95% CI (− 2.94, − 0.75)), PhenoAge (BETA = − 1.57, 95% CI (− 3.05, − 0.08)), Horvath (BETA = − 1.09 (− 2.14, − 0.04)), and Hannum (BETA = − 1.63, 95% CI (− 2.70, − 0.56)). Usual walking pace is significantly associated with a delay in epigenetic aging acceleration (EAA) (P < 0.05). Moreover, the direction of effect predicted by the gene remained consistent across RAPS outcomes and sensitivity MR analyses. There is a lack of robust causal relationships between other walking conditions, such as walking duration and walking frequency, on EAA (P > 0.05). Conclusion: Our evidence demonstrates that a higher usual walking pace is associated with a deceleration of the acceleration of all four classical epigenetic clocks acceleration. Key messages: In recent years, observational studies have found that there is a correlation between walking and aging, but the specific relationship is not clear We used a Mendelian randomization approach to test the causal effect of walking and sedentarism on epigenetic clock acceleration Mendelian randomization studies have found that faster walking speed may delay physiological aging through causal analysis at the genetic level [ABSTRACT FROM AUTHOR]

Background: Healthy sleep is vital for maintaining optimal mental and physical health. Accumulating evidence suggests that sleep loss and disturbances play a significant role in the biological aging process, early onset of disease, and reduced lifespan. While numerous studies have explored the association between biological aging and its drivers, only a few studies have examined its relationship with sleep quality. In this study, we investigated the associations between sleep quality and epigenetic age acceleration using whole blood samples from a cohort of 692 Korean adults. Sleep quality of each participant was assessed using the validated Pittsburgh Sleep Quality Index (PSQI), which encompassed seven domains: subjective sleep quality, sleep latency, sleep duration, habitual sleep efficiency, sleep disturbance, use of sleep medication, and daytime dysfunction. Four epigenetic age accelerations (HorvathAgeAccel, HannumAgeAccel, PhenoAgeAccel, and GrimAgeAccel) and the pace of aging, DunedinPACE, were investigated for epigenetic aging estimates. Results: Among the 692 participants (good sleepers [n = 441, 63.7%]; poor sleepers [n = 251, 36.3%]), DunedinPACE was positively correlated with PSQI scores in poor sleepers (γ =0.18, p < 0.01). GrimAgeAccel (β =0.18, p = 0.02) and DunedinPACE (β =0.01, p < 0.01) showed a statistically significant association with PSQI scores only in poor sleepers by multiple linear regression. In addition, every one-point increase in PSQI was associated with a 15% increase in the risk of metabolic syndrome (MetS) among poor sleepers (OR = 1.15, 95% CI = 1.03–1.29, p = 0.011). In MetS components, a positive correlation was observed between PSQI score and fasting glucose (γ = 0.19, p < 0.01). Conclusions: This study suggests that worsening sleep quality, especially in poor sleepers, is associated with accelerated epigenetic aging for GrimAgeAccel and DundinePACE with risk of metabolic syndrome. This finding could potentially serve as a promising strategy for preventing age-related diseases in the future. [ABSTRACT FROM AUTHOR]

Chronic arsenic exposure is a global health hazard significantly associated with the development of deleterious cutaneous changes and increased keratinocyte cancer risk. Although arsenic exposure is associated with broad-scale cellular and molecular changes, gaps exist in understanding how these changes impact the skin and facilitate malignant transformation. Recently developed epigenetic “clocks” can accurately predict chronological, biological and mitotic age, as well as telomere length, on the basis of tissue DNA methylation state. Deviations of predicted from expected age (epigenetic age dysregulation) have been associated with numerous complex diseases, increased all-cause mortality and higher cancer risk. We investigated the ability of these algorithms to detect molecular changes associated with chronic arsenic exposure in the context of associated skin lesions. To accomplish this, we utilized a multi-algorithmic approach incorporating seven “clocks” (Horvath, Skin&Blood, PhenoAge, PCPhenoAge, GrimAge, DNAmTL and epiTOC2) to analyze peripheral blood of pediatric and adult cohorts of arsenic-exposed (n = 84) and arsenic-naïve (n = 33) individuals, among whom n = 18 were affected by skin lesions. Arsenic-exposed adults with skin lesions exhibited accelerated epigenetic (Skin&Blood: + 7.0 years [95% CI 3.7; 10.2], q = 6.8 × 10–4), biological (PhenoAge: + 5.8 years [95% CI 0.7; 11.0], q = 7.4 × 10–2, p = 2.8 × 10–2) and mitotic age (epiTOC2: + 19.7 annual cell divisions [95% CI 1.8; 37.7], q = 7.4 × 10–2, p = 3.2 × 10–2) compared to healthy arsenic-naïve individuals; and accelerated epigenetic age (Skin&Blood: + 2.8 years [95% CI 0.2; 5.3], q = 2.4 × 10–1, p = 3.4 × 10–2) compared to lesion-free arsenic-exposed individuals. Moreover, lesion-free exposed adults exhibited accelerated Skin&Blood age (+ 4.2 [95% CI 1.3; 7.1], q = 3.8 × 10–2) compared to their arsenic-naïve counterparts. Compared to the pediatric group, arsenic-exposed adults exhibited accelerated epigenetic (+ 3.1 to 4.4 years (95% CI 1.2; 6.4], q = 2.4 × 10–4–3.1 × 10–3), biological (+ 7.4 to 7.8 years [95% CI 3.0; 12.1] q = 1.6 × 10–3–2.8 × 10–3) and mitotic age (+ 50.0 annual cell divisions [95% CI 15.6; 84.5], q = 7.8 × 10–3), as well as shortened telomere length (− 0.23 kilobases [95% CI − 0.13; − 0.33], q = 2.4 × 10–4), across all seven algorithms. We demonstrate that lifetime arsenic exposure and presence of arsenic-associated skin lesions are associated with accelerated epigenetic, biological and mitotic age, and shortened telomere length, reflecting altered immune signaling and genomic regulation. Our findings highlight the usefulness of DNA methylation-based algorithms in identifying deleterious molecular changes associated with chronic exposure to the heavy metal, serving as potential prognosticators of arsenic-induced cutaneous malignancy. [ABSTRACT FROM AUTHOR]

INTRODUCTION: This study investigated whether epigenetic age acceleration (AA) is associated with the change in cognitive function and the risk of incident dementia over 9 years, separately in males and females. METHODS: Six epigenetic AA measures, including GrimAge, were estimated in baseline blood samples from 560 Australians aged ≥70 years (50.7% female). Cognitive assessments included global function, episodic memory, executive function, and psychomotor speed. Composite cognitive scores were also generated. Dementia (Diagnostic and Statistical Manual for Mental Disorders – IV [DSM‐IV] criteria) was adjudicated by international experts. RESULTS: Associations between epigenetic AA and cognitive performance over‐time varied by sex. In females only, GrimAA/Grim2AA was associated with worse delayed recall, composite cognition, and composite memory (adjusted‐beta ranged from –0.1372 to –0.2034). In males only, GrimAA/Grim2AA was associated with slower processing speed (adjusted‐beta, –0.3049) and increased dementia risk (adjusted hazard ratios [HRs], 1.78 and 2.00, respectively). DISCUSSION: Epigenetic AA is associated with cognitive deterioration in later life but with evidence of sex‐specific associations. Highlights: Epigenetic age acceleration was associated with cognitive deterioration over time.However, these associations differed by sex.In females, accelerated GrimAge appeared to be a better marker of decline in memory.In males, accelerated GrimAge was associated with slower processing speed over time.Association between accelerated GrimAge and dementia risk was found only in males. [ABSTRACT FROM AUTHOR]

Abstract Background Dyslipidemia, which is characterized by an unfavorable lipid profile, is a key risk factor for cardiovascular disease (CVD). Understanding the relationships between epigenetic aging and lipid levels may help guide early prevention and treatment efforts for dyslipidemia. Methods We used weighted linear regression to cross-sectionally investigate the associations between five measures of epigenetic age acceleration estimated from whole blood DNA methylation (HorvathAge Acceleration, HannumAge Acceleration, PhenoAge Acceleration, GrimAge Acceleration, and DunedinPACE) and four blood lipid measures (total cholesterol (TC), LDL-C, HDL-C, and triglycerides (TG)) in 3,813 participants (mean age = 70 years) from the Health and Retirement Study (HRS). As a sensitivity analysis, we examined the same associations in participants who fasted prior to the blood draw (n = 2,531) and in participants who did not take lipid-lowering medication (n = 1,869). Using interaction models, we also examined whether demographic factors including age, sex, and educational attainment modified the relationships between epigenetic age acceleration and blood lipids. Results After adjusting for age, race/ethnicity, sex, fasting status, and lipid-lowering medication use, greater epigenetic age acceleration was associated with lower TC, HDL-C, and LDL-C, and higher TG (p

Background Epigenetic ageing is among the most promising ageing biomarkers and may be a useful marker of physical function decline, beyond chronological age. This study investigated whether epigenetic age acceleration (AA) is associated with the change in frailty scores over 7 years and the 7-year risk of incident frailty and persistent Activities of Daily Living (ADL) disability among 560 Australians (50.7% females) aged ≥70 years. Methods Seven AA indices, including GrimAge, GrimAge2, FitAge and DunedinPACE, were estimated from baseline peripheral-blood DNA-methylation. Frailty was assessed using both the 67-item deficit-accumulation frailty index (FI) and Fried phenotype (Fried). Persistent ADL disability was defined as loss of ability to perform one or more basic ADLs for at least 6 months. Linear mixed models and Cox proportional-hazard regression models were used as appropriate. Results Accelerated GrimAge, GrimAge2, FitAge and DunedinPACE at baseline were associated with increasing FI scores per year (adjusted-Beta ranged from 0.0015 to 0.0021, P  < 0.05), and accelerated GrimAge and GrimAge2 were associated with an increased risk of incident FI-defined frailty (adjusted-HRs 1.43 and 1.39, respectively, P  < 0.05). The association between DunedinPACE and the change in FI scores was stronger in females (adjusted-Beta 0.0029, P 0.001 than in males (adjusted-Beta 0.0002, P 0.81). DunedinPACE, but not the other AA measures, was also associated with worsening Fried scores (adjusted-Beta 0.0175, P 0.04). No associations were observed with persistent ADL disability. Conclusion Epigenetic AA in later life is associated with increasing frailty scores per year and the risk of incident FI-defined frailty. [ABSTRACT FROM AUTHOR]

Background: Dyslipidemia, which is characterized by an unfavorable lipid profile, is a key risk factor for cardiovascular disease (CVD). Understanding the relationships between epigenetic aging and lipid levels may help guide early prevention and treatment efforts for dyslipidemia. Methods: We used weighted linear regression to cross-sectionally investigate the associations between five measures of epigenetic age acceleration estimated from whole blood DNA methylation (HorvathAge Acceleration, HannumAge Acceleration, PhenoAge Acceleration, GrimAge Acceleration, and DunedinPACE) and four blood lipid measures (total cholesterol (TC), LDL-C, HDL-C, and triglycerides (TG)) in 3,813 participants (mean age = 70 years) from the Health and Retirement Study (HRS). As a sensitivity analysis, we examined the same associations in participants who fasted prior to the blood draw (n = 2,531) and in participants who did not take lipid-lowering medication (n = 1,869). Using interaction models, we also examined whether demographic factors including age, sex, and educational attainment modified the relationships between epigenetic age acceleration and blood lipids. Results: After adjusting for age, race/ethnicity, sex, fasting status, and lipid-lowering medication use, greater epigenetic age acceleration was associated with lower TC, HDL-C, and LDL-C, and higher TG (p < 0.05), although the effect sizes were relatively small (e.g., < 7 mg/dL of TC per standard deviation in epigenetic age acceleration). GrimAge acceleration and DunedinPACE associations with all lipids remained significant after further adjustment for body mass index, smoking status, and educational attainment. These associations were stronger in participants who fasted and who did not use lipid-lowering medication, particularly for LDL-C. We observed the largest number of interactions between DunedinPACE and demographic factors, where the associations with lipids were stronger in younger participants, females, and those with higher educational attainment. Conclusion: Multiple measures of epigenetic age acceleration are associated with blood lipid levels in older adults. A greater understanding of how these associations differ across demographic groups can help shed light on the relationships between aging and downstream cardiovascular diseases. The inverse associations between epigenetic age and TC and LDL-C could be due to sample limitations or non-linear relationships between age and these lipids, as both TC and LDL-C decrease faster at older ages. [ABSTRACT FROM AUTHOR]

DNA methylation (DNAm) clocks hold promise for measuring biological age, useful for guiding clinical interventions and forensic identification. This study compared the commonly used DNAm clocks, using DNA methylation and SNP data generated from nearly 1000 human blood or buccal swab samples. We evaluated different preprocessing methods for age estimation, investigated the association of epigenetic age acceleration (EAA) with various lifestyle and sociodemographic factors, and undertook a series of novel genome-wide association analyses for different EAA measures to find associated genetic variants. Our results highlighted the Skin&Blood clock with ssNoob normalization as the most accurate predictor of chronological age. We provided novel evidence for an association between the practice of yoga and a reduction in the pace of aging (DunedinPACE). Increased sleep and physical activity were associated with lower mortality risk score (MRS) in our dataset. University degree, vegetable consumption, and coffee intake were associated with reduced levels of epigenetic aging, whereas smoking, higher BMI, meat consumption, and manual occupation correlated well with faster epigenetic aging, with FitAge, GrimAge, and DunedinPACE clocks showing the most robust associations. In addition, we found a novel association signal for SOCS2 rs73218878 (p = 2.87 × 10−8) and accelerated GrimAge. Our study emphasizes the importance of an optimized DNAm analysis workflow for accurate estimation of epigenetic age, which may influence downstream analyses. The results support the influence of genetic background on EAA. The associated SOCS2 is a member of the suppressor of cytokine signaling family known for its role in human longevity. The reported association between various risk factors and EAA has practical implications for the development of health programs to improve quality of life and reduce premature mortality associated with age-related diseases. [ABSTRACT FROM AUTHOR]

Abstract INTRODUCTION This study investigated whether epigenetic age acceleration (AA) is associated with the change in cognitive function and the risk of incident dementia over 9 years, separately in males and females. METHODS Six epigenetic AA measures, including GrimAge, were estimated in baseline blood samples from 560 Australians aged ≥70 years (50.7% female). Cognitive assessments included global function, episodic memory, executive function, and psychomotor speed. Composite cognitive scores were also generated. Dementia (Diagnostic and Statistical Manual for Mental Disorders – IV [DSM‐IV] criteria) was adjudicated by international experts. RESULTS Associations between epigenetic AA and cognitive performance over‐time varied by sex. In females only, GrimAA/Grim2AA was associated with worse delayed recall, composite cognition, and composite memory (adjusted‐beta ranged from –0.1372 to –0.2034). In males only, GrimAA/Grim2AA was associated with slower processing speed (adjusted‐beta, –0.3049) and increased dementia risk (adjusted hazard ratios [HRs], 1.78 and 2.00, respectively). DISCUSSION Epigenetic AA is associated with cognitive deterioration in later life but with evidence of sex‐specific associations. Highlights Epigenetic age acceleration was associated with cognitive deterioration over time. However, these associations differed by sex. In females, accelerated GrimAge appeared to be a better marker of decline in memory. In males, accelerated GrimAge was associated with slower processing speed over time. Association between accelerated GrimAge and dementia risk was found only in males.

BackgroundMarijuana is the third most commonly used drug in the USA and efforts to legalize it for medical and recreational use are growing. Despite the increase in use, marijuana's effect on aging remains understudied and understanding the effects of marijuana on molecular aging may provide novel insights into the role of marijuana in the aging process. We therefore sought to investigate the association between cumulative and recent use of marijuana with epigenetic age acceleration (EAA) as estimated from blood DNA methylation.ResultsA random subset of participants from The Coronary Artery Risk Development in Young Adults (CARDIA) Study with available whole blood at examination years (Y) 15 and Y20 underwent epigenomic profiling. Four EAA estimates (intrinsic epigenetic age acceleration, extrinsic epigenetic age acceleration, PhenoAge acceleration, and GrimAge acceleration) were calculated from DNA methylation levels measured at Y15 and Y20. Ever use and cumulative marijuana-years were calculated from the baseline visit to Y15 and Y20, and recent marijuana use (both any and number of days of use in the last 30 days) were calculated at Y15 and Y20. Ever use of marijuana and each additional marijuana-year were associated with a 6-month (P

Abstract Background People living with HIV (PLHIV) on effective antiretroviral therapy are living near-normal lives. Although they are less susceptible to AIDS-related complications, they remain highly vulnerable to non-communicable diseases. In this exploratory study of older PLHIV (OPLHIV) in Eswatini, we investigated whether epigenetic aging (i.e., the residual between regressing epigenetic age on chronological age) was associated with HIV-related parameters, and whether lifestyle factors modified these relationships. We calculated epigenetic aging focusing on the Horvath, Hannum, PhenoAge and GrimAge epigenetic clocks, and a pace of biological aging biomarker (DunedinPACE) among 44 OPLHIV in Eswatini. Results Age at HIV diagnosis was associated with Hannum epigenetic age acceleration (EAA) (β-coefficient [95% Confidence Interval]; 0.53 [0.05, 1.00], p = 0.03) and longer duration since HIV diagnosis was associated with slower Hannum EAA (− 0.53 [− 1.00, − 0.05], p = 0.03). The average daily dietary intake of fruits and vegetables was associated with DunedinPACE (0.12 [0.03, 0.22], p = 0.01). The associations of Hannum EAA with the age at HIV diagnosis and duration of time since HIV diagnosis were attenuated when the average daily intake of fruits and vegetables or physical activity were included in our models. Diet and self-perceived quality of life measures modified the relationship between CD4+ T cell counts at participant enrollment and Hannum EAA. Conclusions Epigenetic age is more advanced in OPLHIV in Eswatini in those diagnosed with HIV at an older age and slowed in those who have lived for a longer time with diagnosed HIV. Lifestyle and quality of life factors may differentially affect epigenetic aging in OPLHIV. To our knowledge, this is the first study to assess epigenetic aging in OPLHIV in Eswatini and one of the few in sub-Saharan Africa.

ObjectiveSubjective social status (SSS), an individual's assessment of their own social status in relation to others, is associated with health and mortality independently of objective SES; however, no studies have tested whether SSS influences epigenetic aging. The current study examines if SSS is associated with epigenetic age acceleration in both Black and White women, independently of objective SES measured during both childhood and adulthood.MethodFor 9- and 10-year-old Black and White girls, parental education and annual household income was obtained. At ages 39-42, 361 participants (175 Black, 186 White) reported their current education, household income, and SSS, and provided saliva to assess age acceleration using the GrimAge epigenetic clock. Linear regression estimated the association of SSS with epigenetic age acceleration, controlling for objective SES (current education, current income, parents' education, income during childhood), smoking, and counts of cell types.ResultsWhen all objective SES variables were included in the model, SSS remained significantly associated with epigenetic age acceleration, b = - 0.31, p = .003, ß = - 0.15. Black women had significantly greater age acceleration than White women, (t(359) = 5.20, p > .001, d = 0.55) but race did not moderate the association between SSS and epigenetic age acceleration.ConclusionsWomen who rated themselves lower in SSS had greater epigenetic age acceleration, regardless of income and education. There was no difference by race for this association.

Investigate associations of maternal social experiences with offspring epigenetic age acceleration (EAA) from birth through mid-childhood among 205 mother-offspring dyads of minoritized racial and ethnic groups. We used linear regression to examine associations of maternal experiences of racial bias or discrimination (0 = none, 1–2 = intermediate, or 3+ = high), social support (tertile 1 = low, 2 = intermediate, 3 = high), and socioeconomic status index (tertile 1 = low, 2 = intermediate, 3 = high) during the prenatal period with offspring EAA according to Horvath's Pan-Tissue, Horvath's Skin and Blood, and Intrinsic EAA clocks at birth, 3 years, and 7 years. In comparison to children of women who did not experience any racial bias or discrimination, those whose mothers reported highest levels of racial bias or discrimination had lower Pan-Tissue clock EAA in early (−0.50 years; 90% CI: −0.91, −0.09) and mid-childhood (−0.75 years; −1.41, −0.08). We observed similar associations for the Skin and Blood clock and Intrinsic EAA. Maternal experiences of discrimination were not associated with Pan-Tissue EAA at birth. Neither maternal social support nor socioeconomic status predicted offspring EAA. Children whose mothers experienced higher racial bias or discrimination exhibited slower EAA. Future studies are warranted to confirm these findings and establish associations of early-life EAA with long-term health outcomes. [ABSTRACT FROM AUTHOR]

Exposure to arsenic affects millions of people globally. Changes in the epigenome may be involved in pathways linking arsenic to health or serve as biomarkers of exposure. This study investigated associations between prenatal and early-life arsenic exposure and epigenetic age acceleration (EAA) in adults, a biomarker of morbidity and mortality. DNA methylation was measured in peripheral blood mononuclear cells (PBMCs) and buccal cells from 40 adults (median age = 49 years) in Chile with and without high prenatal and early-life arsenic exposure. EAA was calculated using the Horvath, Hannum, PhenoAge, skin and blood, GrimAge, and DNA methylation telomere length clocks. We evaluated associations between arsenic exposure and EAA using robust linear models. Participants classified as with and without arsenic exposure had a median drinking water arsenic concentration at birth of 555 and 2 μg/l, respectively. In PBMCs, adjusting for sex and smoking, exposure was associated with a 6-year PhenoAge acceleration [B (95% CI) = 6.01 (2.60, 9.42)]. After adjusting for cell-type composition, we found positive associations with Hannum EAA [B (95% CI) = 3.11 (0.13, 6.10)], skin and blood EAA [B (95% CI) = 1.77 (0.51, 3.03)], and extrinsic EAA [B (95% CI) = 4.90 (1.22, 8.57)]. The association with PhenoAge acceleration in buccal cells was positive but not statistically significant [B (95% CI) = 4.88 (-1.60, 11.36)]. Arsenic exposure limited to early-life stages may be associated with biological aging in adulthood. Future research may provide information on how EAA programmed in early life is related to health.

Abstract Background Aging has been reported as a major risk factor for severe symptoms and higher mortality rates in COVID-19 patients. Molecular hallmarks such as epigenetic alterations and telomere attenuation reflect the biological process of aging. Epigenetic clocks have been shown to be valuable tools for measuring biological age in various tissues and samples. As such, these epigenetic clocks can determine accelerated biological aging and time-to-mortality across various tissues. Previous reports have shown accelerated biological aging and telomere attrition acceleration following SARS-CoV-2 infection. However, the effect of accelerated epigenetic aging on outcome (death/recovery) in COVID-19 patients with acute respiratory distress syndrome (ARDS) has not been well investigated. Results In this study, we measured DNA methylation age and telomere attrition in 87 severe COVID-19 cases with ARDS under mechanical ventilation. Furthermore, we compared dynamic changes in epigenetic aging across multiple time points until recovery or death. Epigenetic age was measured using the Horvath, Hannum, DNAm skin and blood, GrimAge, and PhenoAge clocks, whereas telomere length was calculated using the surrogate marker DNAmTL. Our analysis revealed significant accelerated epigenetic aging but no telomere attrition acceleration in severe COVID-19 cases. In addition, we observed epigenetic age deceleration at inclusion versus end of follow-up in recovered but not in deceased COVID-19 cases using certain clocks. When comparing dynamic changes in epigenetic age acceleration (EAA), we detected higher EAA using both the Horvath and PhenoAge clocks in deceased versus recovered patients. The DNAmTL measurements revealed telomere attrition acceleration in deceased COVID-19 patients between inclusion and end of follow-up and a significant change in dynamic telomere attrition acceleration when comparing patients who recovered versus those who died. Conclusions EAA and telomere attrition acceleration were associated with treatment outcomes in hospitalized COVID-19 patients with ARDS. A better understanding of the long-term effects of EAA in COVID-19 patients and how they might contribute to long COVID symptoms in recovered individuals is urgently needed.

Abstract Background Epigenetic clocks constructed from DNA methylation patterns have emerged as excellent predictors of aging and aging-related health outcomes. Iron, a crucial element, is meticulously regulated within organisms, a phenomenon referred as iron homeostasis. Previous researches have demonstrated the sophisticated connection between aging and iron homeostasis. However, their causal relationship remains relatively unexplored. Results Through two-sample Mendelian randomization (MR) utilizing the random effect inverse variance weighted (IVW) method, each standard deviation (SD) increase in serum iron was associated with increased GrimAge acceleration (GrimAA, BetaIVW = 0.27, P = 8.54E−03 in 2014 datasets; BetaIVW = 0.31, P = 1.25E−02 in 2021 datasets), HannumAge acceleration (HannumAA, BetaIVW = 0.32, P = 4.50E−03 in 2014 datasets; BetaIVW = 0.32, P = 8.03E−03 in 2021 datasets) and Intrinsic epigenetic age acceleration (IEAA, BetaIVW = 0.34, P = 5.33E−04 in 2014 datasets; BetaIVW = 0.49, P = 9.94E−04 in 2021 datasets). Similar results were also observed in transferrin saturation. While transferrin manifested a negative association with epigenetic age accelerations (EAAs) sensitivity analyses. Besides, lack of solid evidence to support a causal relationship from EAAs to iron-related biomarkers. Conclusions The results of present investigation unveiled the causality of iron overload on acceleration of epigenetic clocks. Researches are warranted to illuminate the underlying mechanisms and formulate strategies for potential interventions.

BackgroundCardiovascular health (CVH) has been defined by the American Heart Association (AHA) as the presence of the "Life's Simple 7" ideal lifestyle and clinical factors. CVH is known to predict longevity and freedom from cardiovascular disease, the leading cause of death for women in the United States. DNA methylation markers of aging have been aggregated into a composite epigenetic age score, which is associated with cardiovascular morbidity and mortality. However, it is unknown whether poor CVH is associated with acceleration of aging as measured by DNA methylation markers in epigenetic age.Methods and resultsWe performed a cross-sectional analysis of racially/ethnically diverse post-menopausal women enrolled in the Women's Health Initiative cohort recruited between 1993 and 1998. Epigenetic age acceleration (EAA) was calculated using DNA methylation data on a subset of participants and the published Horvath and Hannum methods for intrinsic and extrinsic EAA. CVH was calculated using the AHA measures of CVH contributing to a 7-point score. We examined the association between CVH score and EAA using linear regression modeling adjusting for self-reported race/ethnicity and education. Among the 2,170 participants analyzed, 50% were white and mean age was 64 (7 SD) years. Higher or more favorable CVH scores were associated with lower extrinsic EAA (~ 6 months younger age per 1 point higher CVH score, p

Epigenetic biomarkers of accelerated aging have been widely used to predict disease risk and may enhance our understanding of biological mechanisms between early-life adversity and disparities in aging. With respect to childhood adversity, most studies have used parental education or childhood disadvantage and/or have not examined the role played by socioemotional or physical abuse and trauma in epigenetic profiles at older ages. This study leveraged data from the Multi-Ethnic Study of Atherosclerosis (MESA) on experiences of threat and deprivation in participants' early lives (i.e. before the age of 18 years) to examine whether exposure to specific dimensions of early-life adversity is associated with epigenetic profiles at older ages that are indicative of accelerated biological aging. The sample included 842 MESA respondents with DNA methylation data collected between 2010 and 2012 who answered questions on early-life adversities in a 2018–2019 telephone follow-up. We found that experiences of deprivation, but not threat, were associated with later-life GrimAge epigenetic aging signatures that were developed to predict mortality risk. Results indicated that smoking behavior partially mediates this association, which suggests that lifestyle behaviors may act as downstream mechanisms between parental deprivation in early life and accelerated epigenetic aging in later life. [ABSTRACT FROM AUTHOR]

Black American women are disproportionately exposed to adversities that may have an intergenerational impact on mental health. The present study examined whether maternal exposure to adversity and epigenetic age acceleration (EAA; a biomarker of stress exposure) predicts the socioemotional health of her offspring. During pregnancy, 180 Black American women self-reported experiences of childhood adversity and marginalization-related adversity (i.e., racial discrimination and gendered racial stress) and provided a blood sample for epigenetic assessment. At a three-year follow-up visit, women reported their offspring's emotional reactivity (an early indicator of psychopathology) via the CBCL/1.5–5. After adjusting for maternal education and offspring sex, results indicated that greater maternal experiences of childhood trauma (β = 0.21, SE(β) = 0.01; p = 0.01) and racial discrimination (β = 0.14, SE(β) = 0.07; p = 0.049) predicted greater offspring emotional reactivity, as did maternal EAA (β = 0.17, SE(β) = 0.09, p = 0.046). Our findings suggest that maternal EAA could serve as an early biomarker for intergenerational risk conferred by maternal adversity, and that 'maternal adversity' must be defined more broadly to include social marginalization, particularly for Black Americans. [ABSTRACT FROM AUTHOR]

Aberrant DNA methylation (DNAm) is known to be associated with the aetiology of cancer, including colorectal cancer (CRC). In the past, the availability of open access data has been the main driver of innovative method development and research training. However, this is increasingly being eroded by the move to controlled access, particularly of medical data, including cancer DNAm data. To rejuvenate this valuable tradition, we leveraged DNAm data from 1,845 samples (535 CRC tumours, 522 normal colon tissues adjacent to tumours, 72 colorectal adenomas, and 716 normal colon tissues from healthy individuals) from 14 open access studies deposited in NCBI GEO and ArrayExpress. We calculated each sample's epigenetic age (EA) using eleven epigenetic clock models and derived the corresponding epigenetic age acceleration (EAA). For EA, we observed that most first- and second-generation epigenetic clocks reflect the chronological age in normal tissues adjacent to tumours and healthy individuals [e.g., Horvath (r = 0.77 and 0.79), Zhang elastic net (EN) (r = 0.70 and 0.73)] unlike the epigenetic mitotic clocks (EpiTOC, HypoClock, MiAge) (r < 0.3). For EAA, we used PhenoAge, Wu, and the above mitotic clocks and found them to have distinct distributions in different tissue types, particularly between normal colon tissues adjacent to tumours and cancerous tumours, as well as between normal colon tissues adjacent to tumours and normal colon tissue from healthy individuals. Finally, we harnessed these associations to develop a classifier using elastic net regression (with lasso and ridge regularisations) that predicts CRC diagnosis based on a patient's sex and EAAs calculated from histologically normal controls (i.e., normal colon tissues adjacent to tumours and normal colon tissue from healthy individuals). The classifier demonstrated good diagnostic potential with ROC-AUC = 0.886, which suggests that an EAA-based classifier trained on relevant data could become a tool to support diagnostic/prognostic decisions in CRC for clinical professionals. Our study also reemphasises the importance of open access clinical data for method development and training of young scientists. Obtaining the required approvals for controlled access data would not have been possible in the timeframe of this study. [ABSTRACT FROM AUTHOR]

Background: Epigenetic clocks constructed from DNA methylation patterns have emerged as excellent predictors of aging and aging-related health outcomes. Iron, a crucial element, is meticulously regulated within organisms, a phenomenon referred as iron homeostasis. Previous researches have demonstrated the sophisticated connection between aging and iron homeostasis. However, their causal relationship remains relatively unexplored. Results: Through two-sample Mendelian randomization (MR) utilizing the random effect inverse variance weighted (IVW) method, each standard deviation (SD) increase in serum iron was associated with increased GrimAge acceleration (GrimAA, BetaIVW = 0.27, P = 8.54E−03 in 2014 datasets; BetaIVW = 0.31, P = 1.25E−02 in 2021 datasets), HannumAge acceleration (HannumAA, BetaIVW = 0.32, P = 4.50E−03 in 2014 datasets; BetaIVW = 0.32, P = 8.03E−03 in 2021 datasets) and Intrinsic epigenetic age acceleration (IEAA, BetaIVW = 0.34, P = 5.33E−04 in 2014 datasets; BetaIVW = 0.49, P = 9.94E−04 in 2021 datasets). Similar results were also observed in transferrin saturation. While transferrin manifested a negative association with epigenetic age accelerations (EAAs) sensitivity analyses. Besides, lack of solid evidence to support a causal relationship from EAAs to iron-related biomarkers. Conclusions: The results of present investigation unveiled the causality of iron overload on acceleration of epigenetic clocks. Researches are warranted to illuminate the underlying mechanisms and formulate strategies for potential interventions. [ABSTRACT FROM AUTHOR]

This study examined whether children exposed to adversity would exhibit lower epigenetic age acceleration in the context of improved parenting. Children with developmental delays and externalizing behavior problems (N = 62; Mage = 36.26 months; 70.97% boys, 29.03% girls; 71% Latinx, 22.6% Black) were drawn from a larger randomized controlled trial (RCT), which randomized them to receive Internet-delivered parent–child interaction therapy (iPCIT; n = 30) or community referrals as usual (RAU; n = 32). Epigenetic age acceleration was estimated with the pediatric buccal epigenetic clock, using saliva. Adversity was assessed using parent, family, and neighborhood-level cumulative-risk indicators. Adversity interacted with Time 2 (T2) observations of positive and negative-parenting practices to predict epigenetic age acceleration 1.5 years later, regardless of treatment assignment. Children exposed to more adversity displayed lower epigenetic age acceleration when parents evidenced increased positive (b = −0.15, p =.001) and decreased negative (b = −0.12, p =.01) parenting practices. [ABSTRACT FROM AUTHOR]

Abstract Chronic lymphocytic leukemia (CLL) is a mature B cell neoplasm with a predilection for older individuals. While previous studies have identified epigenetic signatures associated with CLL, whether age-related DNA methylation changes modulate CLL relapse remains elusive. In this study, we examined the association between epigenetic age acceleration and time to CLL relapse in a publicly available dataset. DNA methylation profiling of 35 CLL patients prior to initiating chemoimmunotherapy was performed using the Infinium HumanMethylation450 BeadChip. Four epigenetic age acceleration metrics (intrinsic epigenetic age acceleration [IEAA], extrinsic epigenetic age acceleration [EEAA], PhenoAge acceleration [PhenoAA], and GrimAge acceleration [GrimAA]) were estimated from blood DNA methylation levels. Linear, quantile, and logistic regression and receiver operating characteristic curve analyses were conducted to assess the association between each epigenetic age metric and time to CLL relapse. EEAA (p = 0.011) and PhenoAA (p = 0.046) were negatively and GrimAA (p = 0.040) was positively associated with time to CLL relapse. Simultaneous assessment of EEAA and GrimAA in male patients distinguished patients who relapsed early from patients who relapsed later (p = 0.039). No associations were observed with IEAA. These findings suggest epigenetic age acceleration prior to chemoimmunotherapy initiation is associated with time to CLL relapse. Our results provide novel insight into the association between age-related DNA methylation changes and CLL relapse and may serve has biomarkers for treatment relapse, and potentially, treatment selection.

Abstract Background Epigenetic age acceleration (EAA) and epigenetic gestational age acceleration (EGAA) are biomarkers of physiological development and may be affected by the perinatal environment. The aim of this study was to evaluate performance of epigenetic clocks and to identify biological and sociodemographic correlates of EGAA and EAA at birth and in childhood. In the Project Viva pre-birth cohort, DNA methylation was measured in nucleated cells in cord blood (leukocytes and nucleated red blood cells, N = 485) and leukocytes in early (N = 120, median age = 3.2 years) and mid-childhood (N = 460, median age = 7.7 years). We calculated epigenetic gestational age (EGA; Bohlin and Knight clocks) and epigenetic age (EA; Horvath and skin & blood clocks), and respective measures of EGAA and EAA. We evaluated the performance of clocks relative to chronological age using correlations and median absolute error. We tested for associations of maternal-child characteristics with EGAA and EAA using mutually adjusted linear models controlling for estimated cell type proportions. We also tested associations of Horvath EA at birth with childhood EAA. Results Bohlin EGA was strongly correlated with chronological gestational age (Bohlin EGA r = 0.82, p

Abstract Background Previous 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. Results Using 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

Co-occurrence of injection drug use (IDU) and hepatitis C virus infection (HCV) is common in people living with HIV (PLWH) and leads to significantly increased mortality. Epigenetic clocks derived from DNA methylation (DNAm) are associated with disease progression and all-cause mortality. In this study, we hypothesized that epigenetic age mediates the relationships between the co-occurrence of IDU and HCV with mortality risk among PLWH. We tested this hypothesis in the Veterans Aging Cohort Study (n = 927) by using four established epigenetic clocks of DNAm age (i.e., Horvath, Hannum, Pheno, Grim). Compared to individuals without IDU and HCV (IDU-HCV-), participants with IDU and HCV (IDU+HCV+) showed a 2.23-fold greater risk of mortality estimated using a Cox proportional hazards model (hazard ratio: 2.23; 95% confidence interval: 1.62–3.09; p = 1.09E–06). IDU+HCV+ was associated with a significantly increased epigenetic age acceleration (EAA) measured by 3 out of 4 epigenetic clocks, adjusting for demographic and clinical variables (Hannum: p = 8.90E–04, Pheno: p = 2.34E–03, Grim: p = 3.33E–11). Furthermore, we found that epigenetic age partially mediated the relationship between IDU+HCV+ and all-cause mortality, up to a 13.67% mediation proportion. Our results suggest that comorbid IDU with HCV increases EAA in PLWH that partially mediates the increased mortality risk.

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 (n = 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.