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Background: The biological process of aging plays an important role in the progress of liver fibrosis. However, epidemiological evidence about the associations between advanced fibrosis and epigenetic age acceleration (EAA) among individuals with metabolic dysfunction-associated steatotic liver disease (MASLD) is limited., Methods: We utilized publicly available DNA methylation data (GSE180474) for our analysis. Five EAA measures were calculated in this study, including IEAA, PhenoAA, GrimAA, DunedinPACE, and DNAmTLAA. Separate linear regression models were conducted to explore the associations between different fibrosis grades and each measure of EAA., Results: A total of 325 participants were included in this study, with a mean (± SD) age of 48.56 ± 11.50 years. Of these participants, 64.6% with no fibrosis, 16.9% with bridging fibrosis, 11.1% with incomplete cirrhosis, and 7.4% with cirrhosis. After adjusting for demographics and medication status, MASLD individuals with advanced fibrosis were associated with a 5% increase in the pace of aging (DunedinPACE, β = 0.05, 95% CI: 0.03-0.07) and a 10% decrease in DNAmTLAA (β = -0.10, 95% CI: -0.13 to -0.07) compared those without fibrosis. Similarly, higher stages of fibrosis were associated with an increased pace of aging (DunedinPACE, β = 0.02, 95% CI: 0.01-0.03, P trend  < 0.001) and decreased DNAmTLAA (β = -0.05, 95% CI: -0.07 to -0.04, P trend  < 0.001). However, no significant association was found between advanced fibrosis and IEAA, PhenoAA, and GrimAA., Conclusions: Our findings suggest that advanced fibrosis was associated with an accelerated pace of aging, as measured by the third-generation EA measure DunedinPACE, and shorter telomere length, captured by DNAmTLAA, among individuals with MASLD. This finding has potential prognostic implications and suggests EAA may serve as a surrogate marker of therapeutic efficacy in MASLD., Competing Interests: Declarations. Conflict of interest: The authors declare that they have no competing interests., (© 2024. Japanese Society of Gastroenterology.)

Background: Cardiometabolic risk factors among youth are rising. Epigenetic age acceleration, a biomarker for aging and disease-risk, has been associated with adiposity in children, but its association with other cardiometabolic risk markers remains understudied. We employed data from the Health Outcomes and Measures of the Environment (HOME) study, a prospective pregnancy and birth cohort in the greater Cincinnati metropolitan area, to examine whether accelerated epigenetic age at birth as well as accelerated epigenetic age and faster pace of biological aging at age 12 years were associated with higher cardiometabolic risk in adolescents., Results: After adjusting for potential confounders, including estimated cell type proportions, epigenetic gestational age acceleration at birth, derived from the Bohlin, Knight, and Haftorn clocks using cord blood DNA methylation data, was not associated with cardiometabolic risk z-scores or individual cardiometabolic risk score components (visceral fat, leptin to adiponectin ratio, HOMA-IR, triglycerides to HDL-C ratio, HbA1c, or systolic blood pressure) at age 12 years. We also did not observe any associations of epigenetic age acceleration, calculated with Horvath's skin and blood, Hannum's, and Wu's epigenetic clocks using peripheral blood at age 12 years, with these same cardiometabolic risk markers. In contrast, faster pace of biological aging was associated with higher cardiometabolic risk [βs (95% CIs)] cardiometabolic risk score 0.25 (0.07, 0.42); visceral fat 0.21 (0.05, 0.38); and hemoglobin A1c 0.23 (0.05, 0.41) per standard deviation increase in pace of biological aging. Faster pace of biological aging was also positively associated with systolic blood pressure, triglycerides to HDL-C ratio, HOMA-IR, and leptin to adiponectin ratio, although these associations were not statistically significant., Conclusions: Our findings provide evidence that faster pace of biological aging was associated with higher cardiometabolic risk score, visceral fat, and HbA1c at age 12 years. Further research is needed to determine whether these associations persist from adolescence through adulthood., Competing Interests: Declarations Ethics approval and consent to participate The institutional review boards of Cincinnati Children’s Hospital Medical Center, the participating delivery hospitals, and the CDC approved this study. During a face-to-face visit, research assistants explained study protocols to each prospective participant and completed a checklist to ensure women were fully informed. At the 12-year visit, adolescents provided written informed assent after study protocols were explained and their questions answered. Consent for publication Not applicable. Competing interests Dr. Joseph Braun has served as an expert witness for plaintiffs involved in litigation related to PFAS-contaminated drinking water. The other authors declare that they have no competing interests., (© 2024. The Author(s).)

Wildfire-related PM 2.5 has been associated with various adverse health outcomes, but its association with epigenetic aging remains unclear. This study examined the association between wildfire-related PM 2.5 exposure and epigenetic aging using DNA methylation data from a twin and family study. With a within-sibship analysis, we found that each 1 µg/m 3 increase in annual wildfire-related PM 2.5 was associated with a 0.25-year (95 % CI: 0.04, 0.47) increase in GrimAge1 acceleration and a 0.36-year (95 % CI: 0.12, 0.59) increase in GrimAge2 acceleration. Subgroup analyses found that participants aged ≥ 60 years, those with a history of current or former smoking and alcohol consumption, and those living in rural regions exhibited more pronounced epigenetic age acceleration. These findings suggest that wildfire smoke could accelerate biological aging, particularly in vulnerable populations, posing a significant challenge to healthy aging., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 The Authors. Published by Elsevier B.V. All rights reserved.)

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., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier Inc. All rights reserved.)

Objectives: Second to fourth digit ratio is widely known indicator of prenatal sex hormones proportion. Higher prenatal androgenization results in longer fourth finger and lower 2D:4D index. The aim of this study was to determine whether the 2D:4D digit ratio is associated with DNA methylation (DNAm) age dependently on sex., Material and Methods: The study included 182 adults (106 females and 76 males) with a mean age of 51.5 ± 13 years. The investigation consisted of three main parts: a survey, anthropometric dimensions measurements (fingers length) and methylome analysis using collected blood samples. Genome-wide methylation was analyzed using EPIC microarray technology. Epigenetic age and epigenetic age acceleration were calculated using several widely applied algorithms., Results: Males with the female left hand pattern had more accelerated epigenetic age than those with the male pattern as calculated with PhenoAge and DNAmTL clocks., Conclusions: Finger female pattern 2D:4D above or equal to 1 in males is associated with epigenetic age acceleration, indicating that prenatal exposure to estrogens in males may be related to aging process in the later ontogenesis., (© 2024 Wiley Periodicals LLC.)

Objective: To identify differentially methylated regions (DMRs) and assess epigenetic age and instability scores within each cohort of differing income level and educational attainment., Design: Retrospective analysis of epigenetic data., Subjects: 1429 semen samples from participants in the FAZST trial., Exposure: Socio-economic status, approximated by self-reported income, and education level., Main Outcome Measures: Differential sperm DNA methylation, epigenetic age, epigenetic stability RESULTS: There were four significant DMRs associated with the income cohorts and seven associated with the education cohorts, suggesting epigenetic patterns vary with socio-economic status. Adjusted epigenetic age (GLAD values) did not differ significantly in either cohort; however, a higher number of unstable promoters were observed in the lowest education cohort (p-value of 0.006), indicating dysregulation in the epigenome., Conclusion: These findings suggest a biological link between income and education level in sperm epigenetic patterns, which may influence reproductive health. The increase in unstable promoters in the lower education cohorts may contribute to health disparities associated with educational attainment; however, it is important to consider lifestyle factors and environmental exposures as potential underlying causes. Further research is needed to fully elucidate the implications of these epigenetic changes and their relationship to health outcomes., (Copyright © 2024. Published by Elsevier Inc.)

This study aimed to determine the nature of the relationship between the internalized stigma of chronic pain (ISCP), the pace of biological aging, and racial disparities in nonspecific chronic low back pain (CLBP). We used Dunedin Pace of Aging from the Epigenome (DunedinPACE), Horvath's, Hannum's, and PhenoAge clocks to determine the pace of biological aging in adults, ages 18 to 82 years: 74 no pain, 56 low-impact pain, and 76 high-impact pain. Individuals with high-impact pain reported higher levels of ISCP and DunedinPACE compared to those with low-impact or no pain (p < 0.001). There was no significant relationship between ISCP and epigenetic age acceleration from Horvath, Hannum, and PhenoAge clocks ( p  > 0.05). Mediation analysis showed that an association between ISCP and pain severity and interference was mediated by the pace of biological aging ( p  ≤ 0.001). We further found that race moderated the indirect effect of ISCP on pain severity and interference, with ISCP being a stronger positive predictor of the pace of biological aging for non-Hispanic Blacks (NHBs) than for non-Hispanic Whites (NHWs). Future bio-behavioral interventions targeting internalized stigma surrounding chronic pain at various levels are necessary. A deeper understanding of the biological aging process could lead to improvements in managing nonspecific chronic low back pain (CLBP), particularly within underserved minority populations., Competing Interests: The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (© 2024 The Author(s).)

Mathematical algorithms known as "epigenetic clocks" use methylation values at a set of CpG sites to estimate the biological age of an individual in a tissue-specific manner. These clocks have demonstrated both acceleration and delays in epigenetic aging in multiple neuropsychiatric conditions, including schizophrenia and neurodevelopmental disorders such as autism spectrum disorder. However, no study to date has examined epigenetic aging in ADHD despite its status as one of the most prevalent neurodevelopmental conditions, with 1 in 9 children having ever received an ADHD diagnosis in the US. Only a handful of studies have examined epigenetic age in brain tissue from neurodevelopmental conditions, with none focused on ADHD, despite the obvious relevance to pathogenesis. Thus, here we asked if post-mortem brain tissue in those with lifetime histories of ADHD would show accelerated or delayed epigenetic age, as has been found for other neurodevelopmental conditions. We applied four different epigenetic clocks to estimate epigenetic age in individuals with ADHD and unaffected controls from cortical (anterior cingulate cortex, N = 55) and striatal (caudate, N = 56) post-mortem brain tissue, as well as peripheral blood (N = 84) and saliva (N = 112). After determining which epigenetic clock performed best in each tissue, we asked if ADHD was associated with altered biological aging in corticostriatal brain and peripheral tissues. We found that a range of epigenetic clocks accurately predicted chronological age in all tissues. We also found that a diagnosis of ADHD was not significantly associated with differential epigenetic aging, neither for the postmortem ACC or caudate, nor for peripheral tissues. These findings held when accounting for comorbid psychiatric diagnoses, substance use, and stimulant medication. Thus, in this study of epigenetic clocks in ADHD, we find no evidence of altered epigenetic aging in corticostriatal brain regions nor in peripheral tissue. We consider reasons for this unexpected finding, including the limited sampling of brain regions, the age range of individuals studied, and the possibility that processes that accelerate epigenetic age may be counteracted by the developmental delay posited in some models of ADHD., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2024 Shastri, Sudre, Ahn, Jung, Kolachana, Auluck, Elnitski and Shaw.)

Objective: Sickle cell disease (SCD), the most common inherited blood disorder in the United States, is associated with severe psychoneurological symptoms. While epigenetic age acceleration has been linked to psychoneurological symptom burden in other diseases, this connection is unexplored in SCD. This study aimed to assess the association between epigenetic age acceleration and psychoneurological symptom burden in SCD. Methods: In this cross-sectional study, emotional impact, pain impact, sleep impact, social functioning, and cognitive function were assessed in 87 adults living with SCD. DNA methylation data were generated from blood specimens and used to calculate epigenetic age using five clocks (Horvath, Hannum, PhenoAge, GrimAge, & DunedinPACE). Associations between epigenetic age acceleration and symptoms were assessed. Results: The sample ( N = 87) had a mean (SD) chronologic age was 30.6 (8.1) years. Epigenetic age acceleration was associated with several symptom outcomes. GrimAge age acceleration (β = -0.49, p = .03) and increased DunedinPACE (β = -2.23, p = .004) were associated with worse emotional impact scores. PhenoAge (β = -0.32, p = .04) and the GrimAge (β = -0.48, p = .05) age acceleration were associated with worse pain impact scores. Increased DunedinPACE (β = -2.07 p = .04) were associated with worse sleep impact scores. Increased DunedinPACE (β = -2.87, p = .005) was associated with worse social functioning scores. We did not find associations between epigenetic age acceleration and cognitive function in this sample. Conclusion: Epigenetic age acceleration was associated with worse symptom experiences, suggesting the potential for epigenetic age acceleration as a biomarker to aid in risk stratification or targets for intervention to mitigate symptom burden in SCD., Competing Interests: Declaration of Conflicting InterestsThe author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

Elevated plasma total homocysteine (tHcy) is associated with the development of Alzheimer's disease and other forms of dementia. In this study, we report the relationship between tHcy and epigenetic age in older adults with mild cognitive impairment from the VITACOG study. Epigenetic age and rate of aging (ROA) were assessed using various epigenetic clocks, including those developed by Horvath and Hannum, DNAmPhenoAge, and with a focus on Index, a new principal component-based epigenetic clock that, like DNAmPhenoAge, is trained to predict an individual's "PhenoAge." We identified significant associations between tHcy levels and ROA, suggesting that hyperhomocysteinemic individuals were aging at a faster rate. Moreover, Index revealed a normalization of accelerated epigenetic aging in these individuals following treatment with tHcy-lowering B-vitamins. Our results indicate that elevated tHcy is a risk factor for accelerated epigenetic aging, and this can be ameliorated with B-vitamins. These findings have broad relevance for the sizable proportion of the worldwide population with elevated tHcy., (© 2024 Elysium Health, Inc and The Author(s). Aging Cell published by Anatomical Society and John Wiley & Sons Ltd.)

Aging is a complex biological process influenced by various factors, including genetic and environmental influences. In this study, we present BayesAge 2.0, an improved version of our maximum likelihood algorithm designed for predicting transcriptomic age (tAge) from RNA-seq data. Building on the original BayesAge framework, which was developed for epigenetic age prediction, BayesAge 2.0 integrates a Poisson distribution to model count-based gene expression data and employs LOWESS smoothing to capture non-linear gene-age relationships. BayesAge 2.0 provides significant improvements over traditional linear models, such as Elastic Net regression. Specifically, it addresses issues of age bias in predictions, with minimal age-associated bias observed in residuals. Its computational efficiency further distinguishes it from traditional models, as reference construction and cross-validation are completed more quickly compared to Elastic Net regression, which requires extensive hyperparameter tuning. Overall, BayesAge 2.0 represents a notable advance in transcriptomic age prediction, offering a robust, accurate, and efficient tool for aging research and biomarker development., Competing Interests: Conflict of interest The authors declare no conflict of interest.

Background: This study investigated the association of prenatal and early childhood exposure to air pollution with epigenetic age acceleration (EAA) at six years of age using the Environment and Development of Children Cohort (EDC Cohort) MATERIALS & METHODS: Air pollution, including particulate matter [< 2.5 µm (PM 2.5 ) and < 10 µm (PM 10 ) in an aerodynamic diameter], nitrogen dioxide (NO 2 ), ozone (O 3 ), carbon monoxide (CO), and sulfur dioxide (SO 2 ) were estimated based on the residential address for two periods: 1) during the whole pregnancy, and 2) for one year before the follow-up in children at six years of age. The methylation levels in whole blood at six years of age were measured, and the methylation clocks, including Horvath's clock, Horvath's skin and blood clock, PedBE, and Wu's clock, were estimated. Multivariate linear regression models were constructed to analyze the association between EAA and air pollutants., Results: A total of 76 children in EDC cohort were enrolled in this study. During the whole pregnancy, interquartile range (IQR) increases in exposure to PM 2.5 (4.56 μg/m 3 ) and CO (0.156 ppm) were associated with 0.406 years and 0.799 years of EAA (Horvath's clock), respectively. An IQR increase in PM 2.5 (4.76 μg/m 3 ) for one year before the child was six years of age was associated with 0.509 years of EAA (Horvath's clock) and 0.289 years of EAA (Wu's clock). PM 10 (4.30 μg/m 3 ) and O 3 (0.003 ppm) exposure in the period were also associated with EAA in Horvath's clock (0.280 years) and EAA in Horvath's skin and blood clock (0.163 years), respectively., Conclusion: We found that prenatal and childhood exposure to ambient air pollutants is associated with EAA among children. The results suggest that air pollution could induce excess biological aging even in prenatal and early life., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 The Authors. Published by Elsevier Inc. All rights reserved.)

Early-life adversity increases the risk of health problems. Interventions supporting protective and responsive caregiving offer a promising approach to attenuating adversity-induced changes in stress-sensitive biomarkers. This study tested whether participation in an evidence-based dyadic psychosocial intervention, child-parent psychotherapy (CPP), was related to lower epigenetic age acceleration, a trauma-sensitive biomarker of accelerated biological aging that is associated with later health impairment, in a sample of children with trauma histories. Within this quasi-experimental, repeated-measures study, we examined epigenetic age acceleration at baseline and postintervention in a low-income sample of children receiving CPP treatment ( n = 45; age range = 2-6 years; 76% Latino) compared with a weighted, propensity-matched community-comparison sample ( n = 110; age range = 3-6 years; 40% Latino). Baseline epigenetic age acceleration was equivalent across groups. However, posttreatment, epigenetic age acceleration in the treatment group was lower than in the matched community sample. Findings highlight the potential for a dyadic psychosocial intervention to ameliorate accelerated biological aging in trauma-exposed children.

Breast cancer is the most common cancer diagnosed in women and is often treated with chemotherapy. Although previous studies have demonstrated increasing biological age in patients who receive chemotherapy, evaluation of this association with DNA methylation-based markers of biological ageing may provide novel insight into the role of chemotherapy on the ageing process. We therefore sought to investigate the association between chemotherapy and markers of biological ageing as estimated from DNA methylation in women with breast cancer. DNA methylation profiling was performed on peripheral blood collected from 18 patients before and after the first cycle of chemotherapy using the Infinium HumanMethylation450 BeadChip. Six markers of biological age acceleration were estimated from DNA methylation levels. Multiple linear regression analyses were performed to evaluate the association between each metric of biological age acceleration and chemotherapy. After adjusting for chronological age and race, intrinsic epigenetic age acceleration ( p  = 0.041), extrinsic epigenetic age acceleration ( p  = 0.050), PhenoAge acceleration ( p  = 0.001), GrimAge acceleration ( p  < 0.001), and DunedinPACE ( p  = 0.006) were significantly higher and telomere length ( p  = 0.027) was significantly lower following the first cycle of chemotherapy compared to before treatment initiation. These results demonstrate greater biological ageing as estimated from DNA methylation following chemotherapy in women with breast cancer. Our findings illustrate that cytotoxic therapies may modulate the ageing process among breast cancer patients and may also have implications for age-related health conditions in cancer survivors.

Healthcare workers (HCWs) are a high-risk group for hepatitis B virus (HBV) infection. Notably, about 5-10% of the general population does not respond to the HBV vaccination. In this study, we aimed to investigate DNA methylation (DNAm) in order to estimate the biological age of B cells from HCW of both sexes, either responder (R) or non-responder (NR), to HBV vaccination. We used genome-wide DNA methylation data to calculate a set of biomarkers in B cells collected from 41 Rs and 30 NRs between 22 and 62 years old. Unresponsiveness to HBV vaccination was associated with accelerated epigenetic aging (DNAmAge, AltumAge, DunedinPoAm) and was accompanied by epigenetic drift. Female non-responders had higher estimates of telomere length and lower CRP inflammation risk score when compared to responders. Overall, epigenetic differences between responders and non-responders were more evident in females than males. In this study we demonstrated that several methylation DNAm-based clocks and biomarkers are associated with an increased risk of non-response to HBV vaccination, particularly in females. Based on these results, we propose that accelerated epigenetic age could contribute to vaccine unresponsiveness. These insights may help improve the evaluation of the effectiveness of vaccination strategies, especially among HCWs and vulnerable patients.

We examined three generations (grandparents, mothers, and grandchildren) to assess the association between grandparents' educational attainment and their grandchildren's epigenetic-based age acceleration and whether the association was mediated by parental educational attainment and mothers' life course health-related factors. Mothers were recruited to the NHLBI Growth and Health Study at 9-10 years and followed for 10 years (1987-1998). Mothers were then re-contacted three decades later (ages 37-42) to participate in the National Growth and Health Study (NGHS), and health information from their youngest child (i.e., grandchildren; N = 241, ages 2-17) was collected, including their saliva samples to calculate epigenetic age. Five epigenetic-based age acceleration measures were included in this analysis, including four epigenetic clock age accelerations (Horvath, Hannum, GrimAge, and PhenoAge) and DunedinPACE. Grandparents reported their highest education during the initial enrollment interviews. Parental educational attainment and mothers' life course health-related factors (childhood BMI trajectories, adult cardiovascular health behavioral risk score, and adult c-reactive protein) are included as mediators. Grandparents' education was significantly associated with Horvath age acceleration (b = -0.32, SE = 0.14, p = 0.021). Grandchildren with college-degree grandparents showed significantly slower Horvath age accelerations than those without college degrees. This association was partially mediated by parental education and mothers' health-related factors, especially adult cardiovascular health behavioral risk score and CRP, but not mothers' childhood BMI trajectory. This ability to conserve the speed of biological aging may have considerable consequences in shaping health trajectories across the lifespan., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Hypertension is a disease associated with epigenetic aging. However, the pathogenic mechanism underlying this relationship remains unclear. We aimed to characterize the shared genetic architecture of hypertension and epigenetic aging, and identify novel risk loci. Leveraging genome-wide association studies (GWAS) summary statistics of hypertension (129,909 cases and 354,689 controls) and four epigenetic clocks (N = 34,710), we investigated genetic architectures and genetic overlap using bivariate casual mixture model and conditional/conjunctional false discovery rate methods. Functional gene-sets pathway analyses were performed by functional mapping and gene annotation (FUMA) protocol. Hypertension was polygenic with 2.8 K trait-influencing genetic variants. We observed cross-trait genetic enrichment and genetic overlap between hypertension and all four measures of epigenetic aging. Further, we identified 32 distinct genomic loci jointly associated with hypertension and epigenetic aging. Notably, rs1849209 was shared between hypertension and three epigenetic clocks (HannumAge, IEAA, and PhenoAge). The shared loci exhibited a combination of concordant and discordant allelic effects. Functional gene-set analyses revealed significant enrichment in biological pathways related to sensory perception of smell and nervous system processes. We observed genetic overlaps with mixed effect directions between hypertension and all four epigenetic aging measures, and identified 32 shared distinct loci with mixed effect directions, 25 of which were novel for hypertension. Shared genes enriched in biological pathways related to olfaction., (© 2024. The Author(s).)

Background: Chronic pain has been associated with accelerated biological aging, which may be related to epigenetic alterations. We evaluated the association of high-impact pain (ie, pain that limits activities and function) with epigenetic aging, a measure of biological aging, in a nationally representative sample of middle-aged and older adults in the United States., Methods: Cross-sectional analysis of adults 50 years of age and older from the 2016 Health and Retirement Study. Epigenetic aging was derived from 13 epigenetic clocks based on DNA methylation patterns that predict aging correlates of morbidity and mortality. Ordinary least squares regressions were performed to test for differences in the epigenetic clocks, adjusting for the complex survey design, as well as biological, social, and behavioral factors., Results: The analysis consisted of 3 855 adults with mean age of 68.5 years, including 59.8% with no pain and 25.8% with high-impact pain. Consistent with its operational definition, high-impact pain was associated with greater functional and activity limitations. High-impact pain was associated with accelerated epigenetic aging compared to no pain, as measured via second (Zhang, PhenoAge, GrimAge) and third (DunedinPoAm) generation epigenetic clocks. Additionally, GrimAge was accelerated in high-impact pain as compared to low-impact pain., Conclusions: High-impact pain is associated with accelerated epigenetic aging among middle-aged and older adults in the United States. These findings highlight aging-associated epigenetic alterations in high-impact chronic pain and suggest a potential for epigenetic therapeutic approaches for pain management and the preservation of physical function in older adults., (© The Author(s) 2024. Published by Oxford University Press on behalf of The Gerontological Society of America. All rights reserved. For commercial re-use, please contact reprints@oup.com for reprints and translation rights for reprints. All other permissions can be obtained through our RightsLink service via the Permissions link on the article page on our site—for further information please contact journals.permissions@oup.com.)

Introduction : Cardiovascular diseases stand as the leading global cause of mortality. Major modifiable risk factors encompass overweight/obese conditions, high blood pressure, elevated LDL cholesterol, diabetes, smoking, secondhand smoke exposure, unhealthy diet, and physical inactivity. In the present study, we explored the relationship between cardiovascular risk factors and epigenetic age (DNAm age), an estimate reflecting an individual's actual physiological functionality and overall health. Additionally, we assessed the association between DNAm age acceleration and cardiovascular risk, as evaluated through the Framingham risk score (FRS). Methods : The study includes 190 subjects with overweight/obese conditions. We calculated their DNAm age using Zbieć-Piekarska et al.'s DNAm age estimator on five sets of CpGs analyzed in the peripheral leucocytes. Linear regression models were employed to test the associations. Results : Various parameters contributing to increased cardiovascular risk were associated with DNAm age acceleration, such as systolic blood pressure (β = 0.045; SE = 0.019; p = 0.019), heart rate (β = 0.096; SE = 0.032; p = 0.003), blood glucose (β = 0.025; SE = 0.012; p = 0.030), glycated hemoglobin (β = 0.105; SE = 0.042; p = 0.013), diabetes (β = 2.247; SE = 0.841; p = 0.008), and menopausal conditions (β = 2.942; SE = 1.207; p = 0.016), as well as neutrophil (β = 0.100; SE = 0.042; p = 0.018) and granulocyte (β = 0.095; SE = 0.044; p = 0.033) counts. Moreover, DNAm age acceleration raised the FRS (∆% 5.3%, 95% CI 0.8; 9.9, p = 0.019). Conclusion : For the first time, we report that cardiovascular risk factors accelerated DNAm age in a selected population of hypersusceptible individuals with overweight or obesity. Our results highlight the potential of DNAm age acceleration as a biomarker of cumulative effects in cardiovascular risk assessment.

Several studies have indicated that interrupted epigenetic reprogramming using Yamanaka transcription factors (OSKM) can rejuvenate cells from old laboratory animals and humans. However, the potential of OSKM-induced rejuvenation in brain tissue has been less explored. Here, we aimed to restore cognitive performance in 25.3-month-old female Sprague-Dawley rats using OSKM gene therapy for 39 days. Their progress was then compared with the cognitive performance of untreated 3.5-month-old rats as well as old control rats treated with a placebo adenovector. The Barnes maze test, used to assess cognitive performance, demonstrated enhanced cognitive abilities in old rats treated with OSKM compared to old control animals. In the treated old rats, there was a noticeable trend towards improved spatial memory relative to the old controls. Further, OSKM gene expression did not lead to any pathological alterations within the 39 days. Analysis of DNA methylation following OSKM treatment yielded three insights. First, epigenetic clocks for rats suggested a marginally significant epigenetic rejuvenation. Second, chromatin state analysis revealed that OSKM treatment rejuvenated the methylome of the hippocampus. Third, an epigenome-wide association analysis indicated that OSKM expression in the hippocampus of old rats partially reversed the age-related increase in methylation. In summary, the administration of Yamanaka genes via viral vectors rejuvenates the functional capabilities and the epigenetic landscape of the rat hippocampus., (© 2024. The Author(s).)

Harsh parenting has been shown to increase the risk of physical and mental health problems in later life. To improve our understanding of these risks and how they can be mitigated, we investigated associations of harsh parenting with a clinically relevant biomarker, epigenetic age deviation (EAD), using data from a randomized-control trial of the Incredible Years (IY) parenting program. This study included 281 children aged 4-8 years who were screened for heightened externalizing behavior and whose parents were randomly allocated to either IY or care-as-usual (CAU). Parents reported on their own parenting practices and their child's externalizing behavior at baseline and at a follow-up assessment approximately three years later. Epigenetic age, based on the Pediatric Buccal Epigenetic (PedBE) clock, was estimated from child DNA methylation derived from saliva collected at the follow-up assessment. PedBE clock estimates were regressed on chronological age as a measure of EAD. Moderation analyses using multiple regression revealed that harsher parenting at baseline predicted epigenetic age deceleration in children that received CAU (b = -.21, 95% CI[-0.37, -0.05]), but no association was found in children whose parents were allocated to IY (b = -.02, 95% CI [-0.13, 0.19]). These results highlight a prospective association between harsh parenting and children's EAD and indicate a potential ameliorating effect of preventive intervention. Future work is needed to replicate these findings and understand individual differences in children's responses to harsh parenting in relation to epigenetic aging., Competing Interests: Declaration of Competing Interest None, (Copyright © 2024 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Health problems associated with aging are a major public health concern for the future. Aging is a complex process with wide intervariability among individuals. Therefore, there is a need for innovative public health strategies that target factors associated with aging and the development of tools to assess the effectiveness of these strategies accurately. Novel approaches to measure biological age, such as epigenetic clocks, have become relevant. These clocks use non-sequential variable information from the genome and employ mathematical algorithms to estimate biological age based on DNA methylation levels. Therefore, in the present study, we comprehensively review the current status of the epigenetic clocks and their associations across the human phenome. We emphasize the potential utility of these tools in an epidemiological context, particularly in evaluating the impact of public health interventions focused on promoting healthy aging. Our review describes associations between epigenetic clocks and multiple traits across the life and health span. Additionally, we highlighted the evolution of studies beyond mere associations to establish causal mechanisms between epigenetic age and disease. We explored the application of epigenetic clocks to measure the efficacy of interventions focusing on rejuvenation., Competing Interests: Conflicts of Interest The authors declare no financial interests., (Copyright © 2024 Instituto Mexicano del Seguro Social (IMSS). Published by Elsevier Inc. All rights reserved.)

Since their introduction, epigenetic clocks have been extensively used in aging, human disease, and rejuvenation studies. In this article, we report an intriguing pattern: epigenetic age predictions display a 24-h periodicity. We tested a circadian blood sample collection using 17 epigenetic clocks addressing different aspects of aging. Thirteen clocks exhibited significant oscillations with the youngest and oldest age estimates around midnight and noon, respectively. In addition, daily oscillations were consistent with the changes of epigenetic age across different times of day observed in an independant populational dataset. While these oscillations can in part be attributed to variations in white blood cell type composition, cell count correction methods might not fully resolve the issue. Furthermore, some epigenetic clocks exhibited 24-h periodicity even in the purified fraction of neutrophils pointing at plausible contributions of intracellular epigenomic oscillations. Evidence for circadian variation in epigenetic clocks emphasizes the importance of the time-of-day for obtaining accurate estimates of epigenetic age., (© 2024 The Authors. Aging Cell published by Anatomical Society and John Wiley & Sons Ltd.)

Background: Epigenetic Age (EA) is an age estimate, developed using DNA methylation (DNAm) states of selected CpG sites across the genome. Although EA and chronological age are highly correlated, EA may not increase uniformly with time. Departures, known as epigenetic age acceleration (EAA), are common and have been linked to various traits and future disease risk. Limited by available data, most studies investigating these relationships have been cross-sectional - using a single EA measurement. However, the recent growth in longitudinal DNAm studies has led to analyses of associations with EA over time. These studies differ in (i) their choice of model; (ii) the primary outcome (EA vs. EAA); and (iii) in their use of chronological age or age-independent time variables to account for the temporal dynamic. We evaluated the robustness of each approach using simulations and tested our results in two real-world examples, using biological sex and birthweight as predictors of longitudinal EA., Results: Our simulations showed most accurate effect sizes in a linear mixed model or generalized estimating equation, using chronological age as the time variable. The use of EA versus EAA as an outcome did not strongly impact estimates. Applying the optimal model in real-world data uncovered an accelerated EA rate in males and an advanced EA that decelerates over time in children with higher birthweight., Conclusion: Our results can serve as a guide for forthcoming longitudinal EA studies, aiding in methodological decisions that may determine whether an association is accurately estimated, overestimated, or potentially overlooked., Competing Interests: Competing interest The authors have no competing interests.

The circadian rhythm regulates many crucial physiological processes, impacting human aging and aging-related outcomes. Observational evidence links circadian rhythm disturbance to PM 2.5 exposure, yet the underlying DNA methylation mechanisms remain unclear due to limited PM 2.5 -dominated experimental settings. Therefore, we investigated the associations between short-term PM 2.5 exposure and DNA methylation changes of 1188 CpG candidates across circadian genes among 32 young adults in the FDU study, with the validation in 26 individuals from the PKU study. Further mediation analyses tested whether DNA methylation of circadian genes could mediate the influence of PM 2.5 on aging measured by three epigenetic ages: DNAmGrimAge, DunedinPoAm, and the mortality risk score. We identified three CpG sites associated with personal PM 2.5 exposure: cg01248361 ( CSNK2A2 ), cg17728065 ( RORA ), and cg22513396 ( PRKAG2 ). Acute effects of PM 2.5 on the three loci could be mediated by several circulating biomarkers, including MDA and EGF, with up to ∼30% of mediated proportions. Three loci further showed varying potentials in mediating the aging acceleration effect of PM 2.5 . Locus cg17728065 is the key site exhibiting a robust mediating effect (7.54-12.52%) on PM 2.5 -induced aging acceleration. Our findings demonstrated that PM 2.5 , even short-term peaks, could leave imprints on human aging via inducing aberrant temporal fluctuation in circadian homeostasis captured by DNA methylation profiles.

Psoriasis (PsO) is a chronic inflammatory skin condition, often accompanied by psoriatic arthritis (PsA) and linked to various comorbidities and increased mortality rates. This study aimed to explore the relationship between PsO and accelerated biological aging, specifically focusing on epigenetic DNA methylation clocks. Using a matched case-control design, 20 PsO cases were selected along with age, race, and sex-matched 20 controls without PsO from the Skin Disease Biorepository at Brown Dermatology, Inc, Providence, Rhode Island. Blood samples retrieved from both groups were analyzed for DNA methylation, and epigenetic ages were calculated using DNA methylation clocks, including Horvath, Hannum, Pheno, SkinBlood, and Grim ages. Generalized estimation equations were employed to test the differences in epigenetic and chronological ages between PsO cases and controls, as well as within various subgroups in comparison to their respective controls. There were no statistically significant differences in epigenetic ages between PsO cases and controls. However, notably, PsO cases with PsA demonstrated an accelerated PhenoAge, compared to their matched controls. This study represents a pioneering investigation into the potential link between PsO and epigenetic aging, shedding light on the possibility of accelerated epigenetic aging in PsA, possibly associated with heightened inflammatory burden. These findings emphasize the systemic impact of PsA on the aging process, prompting the need for deeper exploration into autoimmune pathways, inflammation, and epigenetic modifications underlying PsO pathogenesis and aging mechanisms. Larger-scale studies with diverse populations are imperative to discern PsO subgroups experiencing accelerated biological aging and decipher the intricate interplay between PsO, inflammation, and aging pathways., (© 2024. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)

Biological age is a concept that uses bio-physiological parameters to account for individual heterogeneity in the biological processes driving aging and aims to enhance the prediction of age-related clinical conditions compared to chronological age. Although engaging in healthy lifestyle behaviors has been linked to a lower mortality risk and a reduced incidence of chronic diseases, it remains unclear to what extent these health benefits result from slowing the pace of the biological aging process. This short review summarized how modifiable lifestyle factors - including diet, physical activity, smoking, alcohol consumption, and the aggregate of multiple healthy behaviors - were associated with established estimates of biological age based on clinical or cellular/molecular markers, including Klemera-Doubal Method biological age, homeostatic dysregulation, phenotypic age, DNA methylation age, and telomere length. In brief, the available studies tend to show a consistent association of lifestyle factors with physiological measures of biological age, while findings regarding molecular-based metrics vary. The limited evidence highlights the need for further research in this field, particularly with a life-course approach., Competing Interests: The author has no conflicts of interest., (© The Authors 2024.)

Background: Food insecurity is recognized as a key social determinant of health for older adults. While food insecurity has been associated with morbidity and mortality, few studies have examined how it may contribute to accelerated biological aging. A potential mechanism by which food insecurity may contribute to aging is via epigenetic alterations. We examined the relationship between food insecurity and epigenetic aging, a novel measure of biological aging, in a nationally representative sample of middle-aged and older adults in the United States., Methods: Cross-sectional analysis of adults 50 years of age and older from the 2016 Health and Retirement Study (HRS). Financial food insecurity was self-reported via two questions that ascertained having enough money for food or eating less than they felt they should. Epigenetic aging was measured via epigenetic clocks based on DNA methylation patterns that predict aging correlates of morbidity and mortality. Linear regressions were performed to test for differences in the epigenetic clocks, adjusting for biological, socioeconomic, and behavioral factors., Results: The analysis consisted of 3875 adults with mean age of 68.5 years. A total of 8.1% reported food insecurity. Food insecurity was associated with several characteristics, including younger age, race/ethnic minority, lower income, total wealth, and educational attainment, higher BMI, and less physical activity. Food insecurity was associated with accelerated epigenetic aging compared to food security, as measured via second (Zhang, PhenoAge, GrimAge) and third (DunedinPoAm) generation epigenetic clocks. In particular, food insecurity remained significantly associated with accelerated Zhang (B = 0.09, SE = 0.03, p = 0.011) and GrimAge (B = 0.57, SE = 0.24, p = 0.022) in the fully adjusted models., Conclusions: Food insecurity is associated with accelerated epigenetic aging among middle-aged and older adults in the United States. Food insecurity may contribute to DNA methylation alterations across the genome and biological age acceleration. These findings add to a growing understanding of the influence of socioeconomic status on the epigenome and health in aging., Competing Interests: Declaration of competing interest The authors have no conflicts of interest to declare., (Copyright © 2024 Elsevier Ltd. All rights reserved.)

Epigenetic aging clocks are computational models that predict age using DNA methylation information. Initially, first-generation clocks were developed to make predictions using CpGs that change with age. Over time, next-generation clocks were created using CpGs that relate to both age and health. Since existing next-generation clocks were constructed in blood, we sought to develop a next-generation clock optimized for prediction in cheek swabs, which are non-invasive and easy to collect. To do this, we collected MethylationEPIC data as well as lifestyle and health information from 8045 diverse adults. Using a novel simulated annealing approach that allowed us to incorporate lifestyle and health factors into training as well as a combination of CpG filtering, CpG clustering, and clock ensembling, we constructed CheekAge, an epigenetic aging clock that has a strong correlation with age, displays high test-retest reproducibility across replicates, and significantly associates with a plethora of lifestyle and health factors, such as BMI, smoking status, and alcohol intake. We validated CheekAge in an internal dataset and multiple publicly available datasets, including samples from patients with progeria or meningioma. In addition to exploring the underlying biology of the data and clock, we provide a free online tool that allows users to mine our methylomic data and predict epigenetic age., (© 2024. The Author(s).)

Background: Hair products may be a source of harmful chemicals and have been linked to age-related health outcomes. We investigated whether the use of hair products is related to epigenetic age in a sample of Black (both Hispanic and non-Hispanic) and non-Hispanic White women., Methods: In a subset of 4358 participants aged 35-74 years from the Sister Study, we estimated cross-sectional associations between self-reported use of four chemical hair products (permanent dye, semipermanent dye, straighteners/relaxers, and hair permanents/body waves) in the year before enrollment (2003-2009) and three DNA methylation-based measures of epigenetic age (DunedinPACE, GrimAge age acceleration [GrimAgeAccel], and PhenoAge age acceleration [PhenoAgeAccel]) using survey-weighted multivariable linear regressions. Associations were estimated both overall and by self-identified race and ethnicity, adjusting for chronological age, socioeconomic and lifestyle factors, body mass index, menopausal status, and DNA methylation platform., Results: Associations between the use of hair products and the three epigenetic age measures were largely null. Use of hair permanents/body waves was modestly associated with higher DunedinPACE among all participants ( β ever-never = 0.010; 95% confidence interval [CI] = 0.001, 0.019) and with lower PhenoAgeAccel among Black women ( β ever-never = -1.53; 95% CI = -2.84, -0.21)., Conclusion: In this US-based study, we found little evidence of associations between chemical hair product use and epigenetic age in Black and non-Hispanic White women. Observed associations were modest and largely not supported by dose-response relationships or were inconsistent across epigenetic age measures. Previously observed associations between chemical hair product use and aging-related health outcomes may not be explained by the biological aging pathways captured by DunedinPACE, GrimAgeAccel, or PhenoAgeAccel. Alternative biological pathways are worth investigating in racially diverse samples., Competing Interests: The authors declare that they have no conflicts of interest with regard to the content of this report.

Dynamic changes in genomic DNA methylation patterns govern the epigenetic developmental programs and accompany the organism's aging. Epigenetic clock (eAge) algorithms utilize DNA methylation to estimate the age and risk factors for diseases as well as analyze the impact of various interventions. High-throughput bisulfite sequencing methods, such as reduced-representation bisulfite sequencing (RRBS) or whole genome bisulfite sequencing (WGBS), provide an opportunity to identify the genomic regions of disordered or heterogeneous DNA methylation, which might be associated with cell-type heterogeneity, DNA methylation erosion, and allele-specific methylation. We systematically evaluated the applicability of five scores assessing the variability of methylation patterns by evaluating within-sample heterogeneity (WSH) to construct human blood epigenetic clock models using RRBS data. The best performance was demonstrated by the model based on a metric designed to assess DNA methylation erosion with an MAE of 3.686 years. We also trained a prediction model that uses the average methylation level over genomic regions. Although this region-based model was relatively more efficient than the WSH-based model, the latter required the analysis of just a few short genomic regions and, therefore, could be a useful tool to design a reduced epigenetic clock that is analyzed by targeted next-generation sequencing.

Case presentation: Scientific documentation on lifelong repeated cycles of long-term fasting doesn't exist. We report the case of a 92-year-old man who fasted 3 weeks yearly for 45 years. Results: Body weight and clinical parameters showed cyclic variations, returning to baseline after food reintroduction. Biological age analysis indicated that the patient was 5.9 years younger than his chronological age. Mental and physical health tests documented the absence of frailty, that the patient could function independently, had excellent cognitive functions, and a good mobility. Conclusion: It can be reasonably assumed that this subject have had protective effects from his yearly fasting.

This study investigates the association between epigenetic age acceleration (EAA) derived from DNA methylation and the risk of incident colorectal cancer (CRC). We utilized data from a random population sample of 9,360 individuals (men and women, aged 45-69) from the HAPIEE Study who had been followed up for 16 years. A nested case-control design yielded 35 incident CRC cases and 354 matched controls. Six baseline epigenetic age (EA) measures (Horvath, Hannum, PhenoAge, Skin and Blood (SB), BLUP, and Elastic Net (EN)) were calculated along with their respective EAAs. After adjustment, the odds ratios (ORs) for CRC risk per decile increase in EAA ranged from 1.20 (95% CI: 1.04-1.39) to 1.44 (95% CI: 1.21-1.76) for the Horvath, Hannum, PhenoAge, and BLUP measures. Conversely, the SB and EN EAA measures showed borderline inverse associations with ORs of 0.86-0.87 (95% CI: 0.76-0.99). Tertile analysis reinforced a positive association between CRC risk and four EAA measures (Horvath, Hannum, PhenoAge, and BLUP) and a modest inverse relationship with EN EAA. Our findings from a prospective population-based-case-control study indicate a direct association between incident CRC and four markers of accelerated baseline epigenetic age. In contrast, two markers showed a negative association or no association. These results warrant further exploration in larger cohorts and may have implications for CRC risk assessment and prevention.

Introduction: DNA methylation, specifically the formation of 5-methylcytosine at the C5 position of cytosine, undergoes reproducible changes as organisms age, establishing it as a significant biomarker in aging studies. Epigenetic clocks, which integrate methylation patterns to predict age, often employ linear models based on penalized regression, yet they encounter challenges in handling missing data, count-based bisulfite sequence data, and interpretation. Methods: To address these limitations, we introduce BayesAge, an extension of the scAge methodology originally designed for single-cell DNA methylation analysis. BayesAge employs maximum likelihood estimation (MLE) for age inference, models count data using binomial distributions, and incorporates LOWESS smoothing to capture non-linear methylation-age dynamics. This approach is tailored for bulk bisulfite sequencing datasets. Results: BayesAge demonstrates superior performance compared to scAge. Notably, its age residuals exhibit no age association, offering a less biased representation of epigenetic age variation across populations. Furthermore, BayesAge facilitates the estimation of error bounds on age inference. When applied to down-sampled data, BayesAge achieves a higher coefficient of determination between predicted and actual ages compared to both scAge and penalized regression. Discussion: BayesAge presents a promising advancement in epigenetic age prediction, addressing key challenges encountered by existing models. By integrating robust statistical techniques and tailored methodologies for count-based data, BayesAge offers improved accuracy and interpretability in predicting age from bulk bisulfite sequencing datasets. Its ability to estimate error bounds enhances the reliability of age inference, thereby contributing to a more comprehensive understanding of epigenetic aging processes., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2024 Mboning, Rubbi, Thompson, Bouchard and Pellegrini.)

Background: In observational studies, there exists an association between obesity and epigenetic age as well as telomere length. However, varying and partially conflicting outcomes have notably arisen from distinct studies on this topic. In the present study, two-way Mendelian randomization was used to identify potential causal associations between obesity and epigenetic age and telomeres., Methods: A genome-wide association study was conducted using data from individuals of European ancestry to investigate bidirectional Mendelian randomization (MR) regarding the causal relationships between obesity, as indicated by three obesity indicators (body mass index or BMI, waist circumference adjusted for BMI or WCadjBMI, and waist-to-hip ratio adjusted for BMI or WHRadjBMI), and four epigenetic age measures (HannumAge, HorvathAge, GrimAge, PhenoAge), as well as telomere length. To assess these causal associations, various statistical methods were employed, including Inverse Variance Weighted (IVW), Weighted Median, MR Egger, Weighted Mode, and Simple Mode. To address the issue of multiple testing, we applied the Bonferroni correction. These methods were used to determine whether there is a causal link between obesity and epigenetic age, as well as telomere length, and to explore potential bidirectional relationships. Forest plots and scatter plots were generated to show causal associations between exposures and outcomes. For a comprehensive visualization of the results, leave-one-out sensitivity analysis plots, individual SNP-based forest plots for MR analysis, and funnel plots were included in the presentation of the results., Results: A strong causal association was identified between obesity and accelerated HannumAge, GrimAge, PhenoAge and telomere length shrinkage. The causal relationship between WCadjBMI and PhenoAge acceleration (OR: 2.099, 95%CI: 1.248-3.531, p = 0.005) was the strongest among them. However, only the p-values for the causal associations of obesity with GrimAge, PhenoAge, and telomere length met the criteria after correction using the Bonferroni multiple test. In the reverse MR analysis, there were statistically significant causal associations between HorvathAge, PhenoAge and GrimAge and BMI, but these associations exhibited lower effect sizes, as indicated by their Odds Ratios (ORs). Notably, sensitivity analysis revealed the robustness of the study results., Conclusions: The present findings reveal a causal relationship between obesity and the acceleration of epigenetic aging as well as the reduction of telomere length, offering valuable insights for further scientific investigations aimed at developing strategies to mitigate the aging process in humans., (© 2024. The Author(s).)

Sex hormones are hypothesized to drive sex-specific health disparities. Here, we study the association between sex steroid hormones and DNA methylation-based (DNAm) biomarkers of age and mortality risk including Pheno Age Acceleration (AA), Grim AA, and DNAm-based estimators of Plasminogen Activator Inhibitor 1 (PAI1), and leptin concentrations. We pooled data from three population-based cohorts, the Framingham Heart Study Offspring Cohort, the Baltimore Longitudinal Study of Aging, and the InCHIANTI Study, including 1,062 postmenopausal women without hormone therapy and 1,612 men of European descent. Sex-stratified analyses using a linear mixed regression were performed, with a Benjamini-Hochberg (BH) adjustment for multiple testing. Sex Hormone Binding Globulin (SHBG) was associated with a decrease in DNAm PAI1 among men (per 1 standard deviation (SD): -478 pg/mL; 95%CI: -614 to -343; P:1e-11; BH-P: 1e-10), and women (-434 pg/mL; 95%CI: -589 to -279; P:1e-7; BH-P:2e-6). The testosterone/estradiol (TE) ratio was associated with a decrease in Pheno AA (-0.41 years; 95%CI: -0.70 to -0.12; P:0.01; BH-P: 0.04), and DNAm PAI1 (-351 pg/mL; 95%CI: -486 to -217; P:4e-7; BH-P:3e-6) among men. In men, testosterone was associated with a decrease in DNAm PAI1 (-481 pg/mL; 95%CI: -613 to -349; P:2e-12; BH-P:6e-11). SHBG was associated with lower DNAm PAI1 among men and women. Higher testosterone and testosterone/estradiol ratio were associated with lower DNAm PAI and a younger epigenetic age in men. A decrease in DNAm PAI1 is associated with lower mortality and morbidity risk indicating a potential protective effect of testosterone on lifespan and conceivably cardiovascular health via DNAm PAI1., (© 2023. The Author(s).)

Objective: Mitochondrial dysfunction and nuclear epigenetic alterations, two hallmarks of aging, are associated with aberrant development and complex disease risk. Here, we report a method for the simultaneous assessment of mitochondrial DNA copy number (mtDNA-CN) and DNA methylation age (DNAm age) from the same DNA extraction using quantitative polymerase chain reaction (qPCR) and array data, respectively., Result: We present methods for the concurrent estimation of mtDNA-CN and DNAm age from the same DNA samples. This includes qPCR to estimate mtDNA-CN, representing the number of circular mitochondrial genomes in a cell, and DNA methylation microarray data to estimate the epigenetic age of an individual. Further, we provide a method for the combination of these metrics into a shared metric termed 'mtEpiAge'. This approach provides a valuable tool for exploring the interplay between mitochondrial dysfunction and nuclear epigenetic alterations, and their associations with disease and aging., (© 2024. The Author(s).)

The anti-diabetic drug metformin may promote healthy aging. However, few clinical trials of metformin assessing biomarkers of aging have been completed. In this communication, we retrospectively examined the effect of metformin on epigenetic age using principal component (PC)-based epigenetic clocks, mitotic clocks, and pace of aging in peripheral monocytes and CD8 + T cells from participants in two clinical trials of virologically-suppressed people living with HIV (PLWH) with normal glucose receiving metformin. In a small 24-week clinical trial that randomized participants to receive either adjunctive metformin or observation, we observed significantly decreased PCPhenoAge and PCGrimAge estimates of monocytes from only participants in the metformin arm by a mean decrease of 3.53 and 1.84 years from baseline to Week 24. In contrast, we observed no significant differences in all PC clocks for participants in the observation arm over 24 weeks. Notably, our analysis of epigenetic mitotic clocks revealed significant increases for monocytes in the metformin arm when comparing baseline to Week 24, suggesting an impact of metformin on myeloid cell kinetics. Analysis of a single-arm clinical trial of adjunctive metformin in eight PLWH revealed no significant differences across all epigenetic clocks assessed in CD8 + T cells at 4- and 8-week time points. Our results suggest cell-type-specific myeloid effects of metformin captured by PC-based epigenetic clock biomarkers. Larger clinical studies of metformin are needed to validate these observations and this report highlights the need for further inclusion of PLWH in geroscience trials evaluating the effect of metformin on increasing healthspan and lifespan., (© 2023 The Authors. Aging Cell published by the Anatomical Society and John Wiley & Sons Ltd.)

Objectives: Loneliness may influence aging biomarkers related to cognitive functioning, for example, through accelerated DNA methylation (DNAm) aging., Methods: In the present study, we tested whether six common DNAm age acceleration measures mediated the effects of baseline loneliness and five different longitudinal loneliness trajectories on general cognitive ability, immediate memory recall, delayed memory recall, and processing speed in 1,814 older adults in the Health and Retirement Study., Results: We found that baseline loneliness and individuals who belong to the highest loneliness trajectories had poorer general cognitive ability and memory scores. Only DNAm age acceleration measures that index physiological comorbidities, unhealthy lifestyle factors (e.g., smoking), and mortality risk-mediated effects of baseline loneliness on general cognitive ability and memory functioning but not processing speed. These same DNAm measures mediated effects of the moderate-but-declining loneliness trajectory on cognitive functioning. Additionally, immediate and delayed memory scores were mediated by GrimAge Accel in the lowest and two highest loneliness trajectory groups. Total and mediated effects of loneliness on cognitive functioning outcomes were mainly accounted for by demographic, social, psychological, and physiological covariates, most notably self-rated health, depressive symptomatology, objective social isolation, and body mass index., Discussion: Current findings suggest that DNAm biomarkers of aging, particularly GrimAge Accel, have promise for explaining the prospective association between loneliness and cognitive functioning outcomes., (© The Author(s) 2023. Published by Oxford University Press on behalf of The Gerontological Society of America. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Background: The causal relationship and the direction of the effect between depression and aging remain controversial., Methods: We used a bidirectional two-sample Mendelian randomization analysis to examine the relationship between depression and age proxy indicators. We obtained pooled statistics from genome-wide association studies (GWAS) on depression and the age proxy indicators. We employed five MR analysis methods to address potential biases and ensure robustness of our results, with the inverse variance weighted (IVW) method being the primary outcome. We also conducted outlier exclusion using Radial MR, MRPRESSO, and MR Steiger filters. Additionally, sensitivity analyses were performed to assess heterogeneity and pleiotropy., Results: Our MR analysis revealed that depression causally leads to shortened telomere length (β = - 0.014; P = 0.038), increased frailty index (β = 0.076; P = 0.000), and accelerated GrimAge (β = 0.249; P = 0.024). Furthermore, our findings showed that the frailty index (OR = 1.679; P = 0.001) was causally associated with an increased risk of depression. Additionally, we found that appendicular lean mass (OR = 0.929; P = 0.000) and left-hand grip strength (OR = 0.836; P = 0.014) were causally associated with a reduced risk of depression. Sensitivity analyses demonstrated the robustness of our findings., Conclusions: Our study provides evidence that depression contributes to the accelerated aging process, resulting in decreased telomere length, increased frailty index, and accelerated GrimAge. Additionally, we found that the frailty index increases the risk of depression, while appendicular lean mass and left-handed grip strength reduce the risk of depression., (© 2023. The Author(s), under exclusive licence to Springer Nature Switzerland AG.)

Early life is seen as a particularly sensitive period for environmental exposures. Natural space exposure during pregnancy has been associated with offspring health. Epigenetic gestational age acceleration, a discrepancy between clinical and DNA methylation-based gestational age, may underlie these associations. In 1359 mother-newborn pairs from the population-based Generation R Study, we examined the associations of natural space exposure, defined as surrounding greenness, distance to major green and blue (water) space, and size of the blue space during pregnancy with offspring epigenetic gestational age acceleration. Natural space exposure was based on participants' geocoded addresses, and epigenetic gestational age acceleration was calculated from cord blood DNA methylation using Bohlin's and Knight's epigenetic clocks. Sensitivity analyses were conducted in a subgroup of newborns with optimal pregnancy dating, based on last menstrual period. Surrounding greenness, measured in normalized difference vegetation index values, was intermediate (median 0.4, IQR 0.2), and 84% and 56% of the participants had a major green or blue space near their home address, respectively. We did not observe associations of natural space availability during pregnancy with offspring epigenetic gestational age acceleration. This could imply that epigenetic gestational age acceleration in cord blood does not underlie the effects of residential natural space availability in pregnancy on offspring health. Future studies could investigate whether residential natural space availability during pregnancy is associated with offspring differential DNA methylation at other CpGs than those included in the epigenetic gestational clocks.

Background: 'Epigenetic clocks' have been developed to accurately predict chronologic gestational age and have been associated with child health outcomes in prior work. Methods: We meta-analysed results from four prospective U.S cohorts investigating the association between epigenetic age acceleration estimated using blood DNA methylation collected at birth and preschool age Childhood Behavior Checklist (CBCL) scores. Results: Epigenetic ageing was not significantly associated with CBCL total problem scores (β = 0.33, 95% CI: -0.95, 0.28) and DSM-oriented pervasive development problem scores (β = -0.23, 95% CI: -0.61, 0.15). No associations were observed for other DSM-oriented subscales. Conclusions: The meta-analysis results suggest that epigenetic gestational age acceleration is not associated with child emotional and behavioural functioning for preschool age group. These findings may relate to our study population, which includes two cohorts enriched for ASD and one preterm birth cohort.; future work should address the role of epigenetic age in child health in other study populations. Abbreviations: DNAm: DNA methylation; CBCL: Child Behavioral Checklist; ECHO: Environmental Influences on Child Health Outcomes; EARLI: Early Autism Risk Longitudinal Investigation; MARBLES: Markers of Autism Risk in Babies - Learning Early Signs; ELGAN: Extremely Low Gestational Age Newborns; ASD: autism spectrum disorder; BMI: body mass index; DSM: Diagnostic and Statistical Manual of Mental Disorders.

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., Competing Interests: The author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article., (© The Author(s) 2023.)

Background: The relationship between aging and osteoporosis is well established. However, the relationship between the body's physiological age, i.e. epigenetic age, and osteoporosis is not known. Our goal is to analyze the bidirectional causal relationship between epigenetic clocks and osteoporosis using a bidirectional Mendelian randomization study., Methods: We used SNPs closely associated with GrimAge, Hannum, PhenoAge, and HorvathAge in epigenetic age and SNPs closely associated with femoral neck bone mineral density, lumbar spine bone mineral density, and forearm bone mineral density as instrumental variables, respectively, using the inverse variance weighting method and several other MR methods to assess the bidirectional causal relationship between epigenetic age and osteoporosis., Result: There was no evidence of a clear causal relationship of epigenetic age (GrimAge, Hannum, PhenoAge, and HorvathAge) on femoral neck bone mineral density, lumbar spine bone mineral density, and forearm bone mineral density. In reverse Mendelian randomization analysis showed a significant causal effect of lumbar spine bone mineral density on GrimAge: odds ratio (OR) = 0.692, 95% confidence interval (CI) = (0.538-0.890), p = 0.004. The results suggest that a decrease in lumbar spine bone mineral density promotes an acceleration of GrimAge., Conclusion: There was no significant bidirectional causal relationship between epigenetic age and osteoporosis A decrease in lumbar spine bone density may lead to an acceleration of the epigenetic clock "GrimAge". Our study provides partial evidence for a bidirectional causal effect between epigenetic age and Osteoporosis., (© 2023. The Author(s).)

Background: DNA methylation-based measures of biological aging have been associated with air pollution and may link pollutant exposures to aging-related health outcomes. However, evidence is inconsistent and there is little information for Black women., Objective: We examined associations of ambient particulate matter <2.5 μm and <10 μm in diameter (PM 2.5 and PM 10 ) and nitrogen dioxide (NO 2 ) with DNA methylation, including epigenetic aging and individual CpG sites, and evaluated whether associations differ between Black and non-Hispanic White (NHW) women., Methods: Validated models were used to estimate annual average outdoor residential exposure to PM 2.5 , PM 10 , and NO 2 in a sample of self-identified Black (n=633) and NHW (n=3493) women residing in the contiguous US. We used sampling-weighted generalized linear regression to examine the effects of pollutants on six epigenetic aging measures (primary: DunedinPACE, GrimAgeAccel, and PhenoAgeAccel; secondary: Horvath intrinsic epigenetic age acceleration [EAA], Hannum extrinsic EAA, and skin & blood EAA) and epigenome-wide associations for individual CpG sites. Wald tests of nested models with and without interaction terms were used to examine effect measure modification by race/ethnicity., Results: Black participants had higher median air pollution exposure than NHW participants. GrimAgeAccel was associated with both PM 10 and NO 2 among Black participants, (Q4 versus Q1, PM 10 : β=1.09, 95% CI: 0.16-2.03; NO 2 : β=1.01, 95% CI 0.08-1.94) but not NHW participants (p-for-heterogeneity: PM 10 =0.10, NO 2 =0.20). In Black participants, we also observed a monotonic exposure-response relationship between NO 2 and DunedinPACE (Q4 versus Q1, NO 2 : β=0.029, 95% CI: 0.004-0.055; p-for-trend=0.03), which was not observed in NHW participants (p-for-heterogeneity=0.09). In the EWAS, pollutants were significantly associated with differential methylation at 19 CpG sites in Black women and one in NHW women., Conclusions: In a US-wide cohort study, our findings suggest that air pollution is associated with DNA methylation alterations consistent with higher epigenetic aging among Black, but not NHW, women., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Purpose: Epigenetic age and inflammatory markers have been proposed as indicators of severity and mortality in patients with COVID-19. Furthermore, they have been associated with the occurrence of neurological symptoms, psychiatric manifestations, and cognitive impairment. Therefore, we aimed to explore the possible associations between epigenetic age, neuropsychiatric manifestations and inflammatory markers (neutrophil-lymphocyte ratio [NLR], platelet-lymphocyte ratio [PLR], monocyte-lymphocyte ratio [MLR], and systemic immune-inflammation index [SII]) in healthcare personnel with post-COVID condition., Patients and Methods: We applied the Montreal Cognitive Assessment (MoCA) and Mini-Mental State Examination (MMSE) tests to 51 Mexican healthcare workers with post-COVID-19 condition; we also estimated their epigenetic age using the PhenoAge calculator., Results: The participants had a post-COVID condition that lasted a median of 14 months (range: 1-20). High NLR (>1.73) had association with mild cognitive impairment by MMSE (p=0.013). Likewise, high MLR (>0.24) were associated with language domain in MOCA (p=0.046). Low PLR (<103.9) was also related to delayed recall in MOCA (p=0.040). Regarding comorbidities, hypertension was associated with SII (p=0.007), overweight with PLR (p=0.047) and alcoholism was associated with MLR (p=0.043). Interestingly, we observed associations of low PLR (<103.9) and low SII (<1.35) levels with increased duration of post-COVID condition (p=0.027, p=0.031). Likewise, increases in PhenoAge were associated with high levels of SII (OR=1.11, p=0.049), PLR (OR=1.12, p=0.035) and MLR (OR=1.12, p=0.030)., Conclusion: We observed neurocognitive changes related to inflammatory markers and increases in epigenetic age in healthcare personnel with post-COVID-19 condition. Future research is required to assess mental and physical health in individuals with post-COVID-19 symptoms., Competing Interests: The authors report no conflicts of interest in this work., (© 2023 Nolasco-Rosales et al.)

Atrial fibrillation (AF) is the most common arrhythmia in humans. AF is characterized by irregular and increased atrial muscle activation. This high-frequency activation obliterates the synchronous work of the atria and ventricles, reducing myocardial performance, which can lead to severe heart failure or stroke. The risk of developing atrial fibrillation depends largely on the patient's history. Cardiovascular diseases are considered aging-related pathologies; therefore, deciphering the role of telomeres and DNA methylation (mDNA), two hallmarks of aging, is likely to contribute to a better understanding and prophylaxis of AF. In honor of Prof. Elizabeth Blackburn's 75th birthday, we dedicate this review to the discovery of telomeres and her contribution to research on aging.

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., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2023 Widayati, Schneider, Panteleeva, Chernysheva, Hrbkova, Beck, Voloshin and Chervova.)

Background: Genome-wide DNA methylation (DNAme) profiling of the placenta with Illumina Infinium Methylation bead arrays is often used to explore the connections between in utero exposures, placental pathology, and fetal development. However, many technical and biological factors can lead to signals of DNAme variation between samples and between cohorts, and understanding and accounting for these factors is essential to ensure meaningful and replicable data analysis. Recently, "epiphenotyping" approaches have been developed whereby DNAme data can be used to impute information about phenotypic variables such as gestational age, sex, cell composition, and ancestry. These epiphenotypes offer avenues to compare phenotypic data across cohorts, and to understand how phenotypic variables relate to DNAme variability. However, the relationships between placental epiphenotyping variables and other technical and biological variables, and their application to downstream epigenome analyses, have not been well studied., Results: Using DNAme data from 204 placentas across three cohorts, we applied the PlaNET R package to estimate epiphenotypes gestational age, ancestry, and cell composition in these samples. PlaNET ancestry estimates were highly correlated with independent polymorphic ancestry-informative markers, and epigenetic gestational age, on average, was estimated within 4 days of reported gestational age, underscoring the accuracy of these tools. Cell composition estimates varied both within and between cohorts, as well as over very long placental processing times. Interestingly, the ratio of cytotrophoblast to syncytiotrophoblast proportion decreased with increasing gestational age, and differed slightly by both maternal ethnicity (lower in white vs. non-white) and genetic ancestry (lower in higher probability European ancestry). The cohort of origin and cytotrophoblast proportion were the largest drivers of DNAme variation in this dataset, based on their associations with the first principal component., Conclusions: This work confirms that cohort, array (technical) batch, cell type proportion, self-reported ethnicity, genetic ancestry, and biological sex are important variables to consider in any analyses of Illumina DNAme data. We further demonstrate the specific utility of epiphenotyping tools developed for use with placental DNAme data, and show that these variables (i) provide an independent check of clinically obtained data and (ii) provide a robust approach to compare variables across different datasets. Finally, we present a general framework for the processing and analysis of placental DNAme data, integrating the epiphenotype variables discussed here., (© 2023. BioMed Central Ltd., part of Springer Nature.)

Background: Epigenetic clocks are based on DNA methylation levels of several genomic loci and have been developed as indices of biological aging. Studies examining the effects of stressful environmental exposures have shown that stress is associated with differences between epigenetic age and chronological age (i.e., Epigenetic Age acceleration, EA). This pre-registered longitudinal study examined the long-term effects of negative parenting and psychological problems throughout adolescence (ages 13-17 years) on EA in late adolescence (age 17 years) and EA changes from late adolescence to young adulthood (age 25 years). Further, it examined how (change in) EA is related to changes in psychological problems from adolescence to young adulthood., Methods: We used data from a sample of 434 participants followed from age 13 to age 25, with saliva collected at ages 17 and 25. We estimated EA using four commonly used epigenetic clocks and analyzed the data using Structural Equation Modeling., Results: While negative parenting was not related to EA nor change in EA, (change in) EA was related to developmental indices such as externalizing problems and self-concept clarity., Conclusions: Declining psychological well-being during young adulthood was preceded by EA., (© 2023 The Authors. Journal of Child Psychology and Psychiatry published by John Wiley & Sons Ltd on behalf of Association for Child and Adolescent Mental Health.)