DNA Methylation Age Research Articles

Abstract 7005: Distinct DNA methylation patterns between early-onset and average-onset colorectal cancer patients

Abstract Objective: Early onset colorectal cancer (EO CRC) is rising at an alarming rate. While average onset colorectal cancer (AO CRC) affects patients mostly above 65 years of age, EO CRC affects patients under 50 years of age, disproportionately affecting males from low-income communities and racial/ethnic minorities. Chronic inflammation has been identified as a strong contributor to pathogenesis. We hypothesize that methylation of DNA may serve as a potential mechanism associated with chronic inflammation that contributes to the etiology differentially between EO and AO CRC. Methods: Formalin-fixed paraffin-embedded (FFPE) tissue specimens from four AO and EO CRC patients each were retrieved from the Tissue Repository. Paraffin curls containing tumor and adjacent normal tissues were generated from appropriate EO and AO CRC patient tissues. The Qiagen GeneRead DNA FFPE genomic DNA kit was then used to extract the DNA from the paraffin curls. Illumina Methylation EPIC v2.0 kit was used to evaluate DNA methylation (DNAm) patterns after the restoration process from deamination in the fixed/embedded sample using the Uracil-N-Glycosylase enzyme. Unreliable and non-specific probes were removed before statistical analysis for differentially methylated CpG sites. Age acceleration for each tissue was calculated by comparing the estimated DNAm age with chronological age using the Horvath approach. Results: A clear clustering of DNAm patterns by age of onset were observed for both normal and tumor tissues. However, there was no difference when comparing tumor and normal tissues after multiple corrections. Four-way ANCOVA adjusting for race, gender, BMI, and tissue type suggested that age onset was the most significant factor. We also found that age acceleration in EO CRC tissue is greater than in AO CRC. After applying Bonferroni correction, significant differentially methylated regions (DMRs) were found in the promoter and the gene body of SNTB1, NFATC3, SLC25A24, RABGAP1L, WDSUB1, WWOX, SELB, SLC28A3, and PPP6R2 in EO CRC patients when compared to AO CRC. SNTB1 regulates colorectal cancer progression and stemness, while NFATC3 has been associated with inflammation and cancer. Conclusions: The preliminary results from this study showed a significant difference in the DNAm profile of FFPE samples between AO and EO CRC. The finding suggests that epigenetics may play a role in the etiology of CRC, potentially involved in the chronic inflammation pathway. The analysis of a larger patient number is underway to strengthen these findings. Citation Format: L. Joseph Su, Ping-Ching Hsu, Aniruddha Rathod, Yulun Liu, Jacopo Ferruzzi, Syed Kazmi, Emina Huang. Distinct DNA methylation patterns between early-onset and average-onset colorectal cancer patients [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 7005.

Exposure to ambient temperature and heat index in relation to DNA methylation age: A population-based study in Taiwan

BackgroundClimate change caused an increase in ambient temperature in the past decades. Exposure to high ambient temperature could result in biological aging, but relevant studies in a warm environment were lacking. We aimed to study the exposure effects of ambient temperature and heat index (HI) in relation to age acceleration in Taiwan, a subtropical island in Asia. MethodsThe study included 2,084 participants from Taiwan Biobank. Daily temperature and relative humidity data were collected from weather monitoring stations. Individual residential exposure was estimated by ordinary kriging. Moving averages of ambient temperature and HI from 1 to 180 days prior to enrollment were calculated to estimate the exposure effects in multiple time periods. Age acceleration was defined as the difference between DNA methylation age and chronological age. DNA methylation age was calculated by the Horvath’s, Hannum’s, Weidner’s, ELOVL2, FHL2, phenotypic (Pheno), Skin & blood, and GrimAge2 (Grim2) DNA methylation age algorithms. Multivariable linear regression models, generalized additive models (GAMs), and distributed lag non-linear models (DLNMs) were conducted to estimate the effects of ambient temperature and HI exposures in relation to age acceleration. ResultsExposure to high ambient temperature and HI were associated with increased age acceleration, and the associations were stronger in prolonged exposure. The heat stress days with maximum HI in caution (80-90°F), extreme caution (90-103°F), danger (103-124°F), and extreme danger (>124°F) were also associated with increased age acceleration, especially in the extreme danger days. Each extreme danger day was associated with 571.38 (95 % CI: 42.63–1100.13), 528.02 (95 % CI: 36.16–1019.87), 43.9 (95 % CI: 0.28–87.52), 16.82 (95 % CI: 2.36–31.28) and 15.52 (95 % CI: 2.17–28.88) days increase in the Horvath’s, Hannum’s, Weidner’s, Pheno, and Skin & blood age acceleration, respectively. ConclusionHigh ambient temperature and HI may accelerate biological aging.

Methylation risk score in peripheral blood predictive of conversion from mild cognitive impairment to Alzheimer's Disease

Background Alzheimer’s disease (AD) is a neurodegenerative and heterogeneous disorder with complex etiology. Mild cognitive impairment (MCI) may represent an intermediate stage of AD, and the ability to identify MCI patients at greater risk of conversion to AD could guide personalized treatments. This study sought to develop a methylation risk score predictive of conversion from MCI to AD using publicly available blood DNA methylation (DNAm) data. Methods Using blood DNA methylation data from an epigenome-wide association study of AD that included 111 subjects with MCI, a methylation risk score of MCI conversion was created using an elastic-net framework. The elastic-net model was trained with a high-variance subset of the DNAm data, age and sex as predictors. Results The final model included three CpG sites: SLC6A3 (cg09892121) and TRIM62 (cg25342005), with a third (cg17292662) near the genes ATP6V1H and RGS20. A significant difference (p < 0.0001, t-test) was observed in the scores for MCI stable subjects compared with MCI converters. No statistically significant difference was observed between AD subjects and controls, suggesting specificity of the risk score for susceptibility to conversion. Conclusions The ability to identify MCI patients at greater risk of progression could inform early interventions and is a critical component in mitigation strategies for AD. This study provides insight into a potential role for epigenetics in the development of a multi-omic risk score of conversion.

DNA methylation clocks for estimating biological age in Chinese cohorts.

Epigenetic clocks are accurate predictors of human chronological age based on the analysis of DNA methylation (DNAm) at specific CpG sites. However, a systematic comparison between DNA methylation data and other omics datasets has not yet been performed. Moreover, available DNAm age predictors are based on datasets with limited ethnic representation. To address these knowledge gaps, we generated and analyzed DNA methylation datasets from two independent Chinese cohorts, revealing age-related DNAm changes. Additionally, a DNA methylation aging clock (iCAS-DNAmAge) and a group of DNAm-based multi-modal clocks for Chinese individuals were developed, with most of them demonstrating strong predictive capabilities for chronological age. The clocks were further employed to predict factors influencing aging rates. The DNAm aging clock, derived from multi-modal aging features (compositeAge-DNAmAge), exhibited a close association with multi-omics changes, lifestyles, and disease status, underscoring its robust potential for precise biological age assessment. Our findings offer novel insights into the regulatory mechanism of age-related DNAm changes and extend the application of the DNAm clock for measuring biological age and aging pace, providing the basis for evaluating aging intervention strategies.

Mitigating cellular aging and enhancing cognitive functionality: visual arts-mediated Cognitive Activation Therapy in neurocognitive disorders.

The growing phenomenon of population aging is redefining demographic dynamics, intensifying age-related conditions, especially dementia, projected to triple by 2050 with an enormous global economic burden. This study investigates visual arts-mediated Cognitive Activation Therapy (CAT) as a non-pharmacological CAT intervention targets both biological aging [leukocyte telomere length (LTL), DNA methylation age (DNAmAge)] and cognitive functionality. Aligning with a broader trend of integrating non-pharmacological approaches into dementia care. The longitudinal study involved 20 patients with mild to moderate neurocognitive disorders. Cognitive and functional assessments, and biological aging markers -i.e., LTL and DNAmAge- were analyzed before and after CAT intervention. Change in LTL was positively correlated with days of treatment (p =0.0518). LTL significantly elongated after intervention (p =0.0269), especially in men (p =0.0142), correlating with younger age (p =0.0357), and higher education (p =0.0008). DNAmAge remained instead stable post-treatment. Cognitive and functional improvements were observed for Copy of complex geometric figure, Progressive Silhouettes, Position Discrimination, Communication Activities of Daily Living-Second edition, Direct Functional Status (p < 0.0001) and Object decision (p =0.0594), but no correlations were found between LTL and cognitive gains. Visual arts-mediated CAT effectively mitigates cellular aging, especially in men, by elongating LTL. These findings underscore the potential of non-pharmacological interventions in enhancing cognitive and functional status and general well-being in dementia care. Further research with larger and longer-term studies is essential for validation.

Health-related quality of life and DNA methylation-based aging biomarkers among survivors of childhood cancer.

Childhood cancer survivors are at high risk for morbidity and mortality and poor patient-reported outcomes, typically health-related quality of life (HRQOL). However, associations between DNA methylation-based aging biomarkers and HRQOL have not been evaluated. DNA methylation was generated with Infinium EPIC BeadChip on blood-derived DNA (median for age at blood draw = 34.5 years, range = 18.5-66.6 years), and HRQOL was assessed with age at survey (mean = 32.3 years, range = 18.4-64.5 years) from 2206 survivors in the St Jude Lifetime Cohort. DNA methylation-based aging biomarkers, including epigenetic age using multiple clocks (eg, GrimAge) and others (eg, DNAmB2M: beta-2-microglobulin; DNAmADM: adrenomedullin), were derived from the DNAm Age Calculator (https://dnamage.genetics.ucla.edu). HRQOL was assessed using the Medical Outcomes Study 36-Item Short-Form Health Survey to capture 8 domains and physical and mental component summaries. General linear models evaluated associations between HRQOL and epigenetic age acceleration (EAA; eg, EAA_GrimAge) or other age-adjusted DNA methylation-based biomarkers (eg, ageadj_DNAmB2M) after adjusting for age at blood draw, sex, cancer treatments, and DNA methylation-based surrogate for smoking pack-years. All P values were 2-sided. Worse HRQOL was associated with greater EAA_GrimAge (physical component summaries: β = -0.18 years, 95% confidence interval [CI] = -0.251 to -0.11 years; P = 1.85 × 10-5; and 4 individual HRQOL domains), followed by ageadj_DNAmB2M (physical component summaries: β = -0.08 years, 95% CI = -0.124 to -0.037 years; P = .003; and 3 individual HRQOL domains) and ageadj_DNAmADM (physical component summaries: β = -0.082 years, 95% CI = -0.125 to -0.039 years; P = .002; and 2 HRQOL domains). EAA_Hannum (Hannum clock) was not associated with any HRQOL. Overall and domain-specific measures of HRQOL are associated with DNA methylation measures of biological aging. Future longitudinal studies should test biological aging as a potential mechanism underlying the association between poor HRQOL and increased risk of clinically assessed adverse health outcomes.

Epigenetic aging of human blood cells is influenced by the age of the host body.

Allogenic hematopoietic stem cell transplantation is a therapeutic procedure performed over a wide range of donor and recipient age combinations, representing natural experiments of how the age of the recipient affects aging in transplanted donor cells invivo. We measured DNA methylation and epigenetic aging in donors and recipients and found that biological epigenetic clocks are accelerated in cells transplanted into an older body and decelerated in a younger body. This is the first evidence that the age of the circulating environment influences human epigenetic aging invivo.

Young Plasma Rejuvenates Blood DNA Methylation Profile, Extends Mean Lifespan, and Improves Physical Appearance in Old Rats.

There is converging evidence that young blood conveys cells, vesicles, and molecules able to revitalize function and restore organ integrity in old individuals. We assessed the effects of young plasma on the lifespan, epigenetic age, and healthspan of old female rats. Beginning at 25.6 months of age, a group of 9 rats (group T) was intraperitoneally injected with plasma from young rats until their natural death. A group of 8 control rats of the same age received no treatment (group C). Blood samples were collected every other week. Survival curves showed that from age 26 to 30 months, none of the group T animals died, whereas the survival curve of group C rats began to decline at age 26 months. Blood DNAm age versus chronological age showed that DNAm age in young animals increased faster than chronological age, then slowed down, entering a plateau after 27 months. The DNAm age of the treated rats fell below the DNAm age of controls and, in numerical terms, remained consistently lower until natural death. When rats were grouped according to the similarities in their differential blood DNA methylation profile, samples from the treated and control rats clustered in separate groups. Analysis of promoter differential methylation in genes involved in systemic regulatory activities revealed specific GO term enrichment related to the insulin-like factors pathways as well as to cytokines and chemokines associated with immune and homeostatic functions. We conclude that young plasma therapy may constitute a natural, noninvasive intervention for epigenetic rejuvenation and health enhancement.

Developmental origins of psycho-cardiometabolic multimorbidity in adolescence and their underlying pathways through methylation markers: a two-cohort study.

Understanding the biological mechanisms behind multimorbidity patterns in adolescence is important as they may act as intermediary risk factor for long-term health. We aimed to explore relationship between prenatal exposures and adolescent's psycho-cardiometabolic intermediary traits mediated through epigenetic biomarkers, using structural equation modeling (SEM). We used data from mother-child dyads from pregnancy and adolescents at 16-17years from two prospective cohorts: Northern Finland Birth Cohort 1986 (NFBC1986) and Raine Study from Australia. Factor analysis was applied to generate two different latent factor structures: (a) prenatal exposures and (b) adolescence psycho-cardiometabolic intermediary traits. Furthermore, three types of epigenetic biomarkers were included: (1) DNA methylation score for maternal smoking during pregnancy (DNAmMSS), (2) DNAm age estimate PhenoAge and (3) DNAm estimate for telomere length (DNAmTL). Similar factor structure was observed between both cohorts yielding three prenatal factors, namely BMI (Body Mass Index), SOP (Socio-Obstetric-Profile), and Lifestyle, and four adolescent factors: Anthropometric, Insulin-Triglycerides, Blood Pressure, and Mental health. In the SEM pathways, stronger direct effects of F1prenatal-BMI (NFBC1986=β: 0.27; Raine=β: 0.39) and F2prenatal-SOP (β: -0.11) factors were observed on adolescent psycho-cardiometabolic multimorbidity. We observed an indirect effect of prenatal latent factors through epigenetic markers on a psycho-cardiometabolic multimorbidity factor in Raine study (P<0.05). The present study exemplifies an evidence-based approach in two different birth cohorts to demonstrate similar composite structure of prenatal exposures and psycho-cardiometabolic traits (despite cultural, social, and genetic differences) and a common plausible pathway between them through underlying epigenetic markers.

Epigenetic Aging and Musculoskeletal Outcomes in a Cohort of Women Living With HIV.

The relationship between accelerated epigenetic aging and musculoskeletal outcomes in women with HIV (WWH) has not been studied. We measured DNA methylation age using the Infinium MethylationEPIC BeadChip in a cohort from the Women's Interagency HIV Study (n = 190) with measures of bone mineral density (BMD) and physical function. We estimated 6 biomarkers of epigenetic aging-epigenetic age acceleration (EAA), extrinsic EAA, intrinsic EAA, GrimAge, PhenoAge, and DNA methylation-estimated telomere length-and evaluated associations of epigenetic aging measures with BMD and physical function. We also performed epigenome-wide association studies to examine associations of DNA methylation signatures with BMD and physical function. This study included 118 WWH (mean age, 49.7 years; 69% Black) and 72 without HIV (mean age, 48.9 years; 69% Black). WWH had higher EAA (mean ± SD, 1.44 ± 5.36 vs -1.88 ± 5.07; P < .001) and lower DNA methylation-estimated telomere length (7.13 ± 0.31 vs 7.34 ± 0.23, P < .001) than women without HIV. There were no significant associations between accelerated epigenetic aging and BMD. Rather, measures of accelerated epigenetic aging were associated with lower physical function. Accelerated epigenetic aging was observed in WWH as compared with women without HIV and was associated with lower physical function in both groups.

Associations of depression and anxiety symptoms in childhood and adolescence with epigenetic aging

BackgroundChildhood anxiety and depression symptoms are potential risk factors for accelerated biological aging. In child and adolescent twins, we tested whether these symptoms were associated with DNA methylation (DNAm) aging, a measure of biological aging. Methods276 twins (135 pairs, 6 singletons) had DNAm assayed from saliva in middle childhood (mean = 7.8 years). Residuals of five different DNAm age estimates regressed on chronological age were used to indicate accelerated aging. Anxiety and depression symptoms were assessed in middle childhood and early adolescence using the Child Behavior Checklist. Mixed effect regression was used to examine potential relationships between anxiety or depression symptoms, and accelerated DNAm age. MZ twin difference analysis was then utilized to determine if associations were environmentally-driven or due to genetic or shared-environment confounding. ResultsAnxiety and depression symptoms were not associated with accelerated DNAm aging in middle childhood. In early adolescence, only the Wu clock was significant and indicated that each one symptom increase in anxiety symptoms had an associated age acceleration of 0.03 years (~0.4 months; p = 0.019). MZ twin difference analysis revealed non-significant within-pair effects, suggesting genetic and shared environmental influences. LimitationsSample is predominantly male and white. Generalizability to other populations may be limited. ConclusionAccelerated DNAm aging of the Wu clock in middle childhood is associated with anxiety, but not depression, symptoms in early adolescence. Further, this association may be the result of shared genetic and environmental influences. Accelerated DNAm aging may serve as an early risk factor or predictor of later anxiety symptoms.

Self-control is associated with health-relevant disparities in buccal DNA-methylation measures of biological aging in older adults

Self-control is a personality dimension that is associated with better physical health and a longer lifespan. Here, we examined (1) whether self-control is associated with buccal and saliva DNA-methylation (DNAm) measures of biological aging quantified in children, adolescents, and adults, and (2) whether biological aging measured in buccal DNAm is associated with self-reported health. Following preregistered analyses, we computed two DNAm measures of advanced biological age (principal-component PhenoAge and GrimAge Acceleration) and a DNAm measure of pace of aging (DunedinPACE) in buccal samples from the German Socioeconomic Panel Study (SOEP-G[ene], n = 1058, age range 0–72, Mage = 42.65) and saliva samples from the Texas Twin Project (TTP, n = 1327, age range 8–20, Mage = 13.50). We found that lower self-control was associated with advanced biological age in older adults (PhenoAge Acceleration β = − .34, [− .51, − .17], p < .001; GrimAge Acceleration β = − .34, [− .49, − .19], p < .001), but not young adults, adolescents or children. These associations remained statistically robust even after correcting for possible confounders such as socioeconomic contexts, BMI, or genetic correlates of low self-control. Moreover, a faster pace of aging and advanced biological age measured in buccal DNAm were associated with self-reported disease (PhenoAge Acceleration: β = .13 [.06, .19], p < .001; GrimAge Acceleration: β = .19 [.12, .26], p < .001; DunedinPACE: β = .09 [.02, .17], p = .01). However, effect sizes were weaker than observations in blood, suggesting that customization of DNAm aging measures to buccal and saliva tissues may be necessary. Our findings are consistent with the hypothesis that self-control is associated with health via pathways that accelerate biological aging in older adults.

Perceived Experiences of racism in Relation to Genome-Wide DNA Methylation and Epigenetic Aging in the Black Women's Health Study.

African American women have a disproportionate burden of disease compared to US non-Hispanic white women. Exposure to psychosocial stressors may contribute to these health disparities. Racial discrimination, a major stressor for African American women, could affect health through epigenetic mechanisms. We conducted an epigenome-wide association study (EWAS) to examine the association of interpersonal racism (in daily life and in institutional settings) with DNA methylation in blood in 384 participants of the Black Women's Health Study (BWHS). We also evaluated whether a greater number of perceived experiences of racism was associated with epigenetic aging as measured using different methylation clocks. Models were adjusted for chronological age, body mass index, years of education, neighborhood SES, geographic region of residence, alcohol drinking, smoking, and technical covariates. Higher scores of racism in daily life were associated with higher methylation levels at the cg04494873 site in chromosome 5 (β = 0.64%; 95% CI = 0.41%, 0.87%; P = 6.35E-08). We also replicated one CpG site, cg03317714, which was inversely associated with racial discrimination in a previous EWAS among African American women. In the BWHS, higher scores of racism in daily life were associated with lower methylation levels at that CpG site (β = -0.94%; 95% CI = -1.37%, -0.51%; P =2.2E-05). Higher racism scores were associated with accelerated epigenetic aging in more than one methylation clock. Exposure to discriminatory events may affect the epigenome and accelerate biological aging, which may explain in part the earlier onset of disease in African American women.

From apnea to aging: insights into the impact of obstructive sleep apnea and its treatment on DNA methylation and epigenetic aging

From apnea to aging: insights into the impact of obstructive sleep apnea and its treatment on DNA methylation and epigenetic aging

DOP58 Human Leukocyte Antigen drives methylation signatures in primary sclerosing cholangitis but not in IgG4-related sclerosing cholangitis

Abstract Background Primary sclerosing cholangitis (PSC) and IgG4-related sclerosing cholangitis (IgG4-SC) are fibro-inflammatory hepatobiliary conditions, with genetic, environmental, and immunologic risk factors, in which epigenetic alterations may provide insights into pathophysiology and novel biomarkers. Methods Whole blood DNA methylation profiling and genotyping was performed in 70 PSC (57 with PSC and ulcerative colitis (PSC-UC)), 56 IgG4-SC, 66 UC, and 88 healthy controls (HC), with MethylationEPIC and Global Screening arrays (Illumina). UC patients were selected to match the clinical characteristics of UC in the PSC-UC cohort. Methylation data was processed with Minfi and limma, genotyping analysed with Plink, and meQTLs with linear models. Results There were 31, 13 and 8 Holm-significant methylation differences between PSC and controls, IgG4-SC and controls, and UC and controls respectively (8 probes shared). Inflammatory genes (including CEP97, IFNAR1, TXK, and SMAD2) and methylation loci associated with mitochondrial DNA copy number (C5orf36, PYY, and MTRNR2L1) were predominant. Sub-analyses of PSC-UC and PSC without IBD detected 25 and 4 differences with HC respectively (p&amp;lt;0.05). DNA methylation age acceleration was observed in IgG4-SC, but not on PSC, PSC-IBD or UC. MeQTL analyses to identify genetic determinants of methylation revealed a strong HLA signal in PSC but not IgG4-SC, with 19/40 significant findings in 5 clusters (HLA-DRB1, HLA-DPB1, BTNL2, CSNK2B, and SFTA2). There was no overlap with the 36 meQTLs found in IgG4-SC. Using multivariate adaptive shrinkage for meQTLs in PSC, IgG4-SC, and UC yielded 5505 meQTLs with local false discovery rate &amp;lt;0.05 in at least one condition, with 1230 unique to PSC, and 1043 to IgG4-SC. Conclusion We identify characteristic epigenetic alterations in PSC and IgG4-related disease, providing insights into disease pathogenesis; and highlight the potential interaction with germ-line variation.

Simultaneous assessment of mitochondrial DNA copy number and nuclear epigenetic age towards predictive models of development and aging

ObjectiveMitochondrial 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.ResultWe 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.

Exploring the causal association between epigenetic clocks and menopause age: insights from a bidirectional Mendelian randomization study.

Evidence suggests a connection between DNA methylation (DNAm) aging and reproductive aging. However, the causal relationship between DNAm and age at menopause remains uncertain. Employing established DNAm epigenetic clocks, such as DNAm Hannum age acceleration (Hannum), Intrinsic epigenetic age acceleration (IEAA), DNAm-estimated granulocyte proportions (Gran), DNAm GrimAge acceleration (GrimAgeAccel), DNAm PhenoAge acceleration (PhenoAgeAccel), and DNAm-estimated plasminogen activator inhibitor-1 levels (DNAmPAIadjAge), a bidirectional Mendelian randomization (MR) study was carried out to explore the potential causality between DNAm and menopausal age. The primary analytical method used was the inverse variance weighted (IVW) estimation model, supplemented by various other estimation techniques. DNAm aging acceleration or deceleration, as indicated by Hannum, IEAA, Gran, GrimAgeAccel, PhenoAgeAccel, and DNAmPAIadjAge, did not exhibit a statistically significant causal effect on menopausal age according to forward MR analysis. However, there was a suggestive positive causal association between age at menopause and Gran (Beta = 0.0010; 95% confidence interval (CI): 0.0004, 0.0020) in reverse MR analysis. The observed increase in granulocyte DNAm levels in relation to menopausal age could potentially serve as a valuable indicator for evaluating the physiological status at the onset of menopause.

The Impact of Childhood Mental Health and Substance Use on Methylation Aging Into Adulthood

To test whether childhood mental health symptoms, substance use, and early adversity accelerate the rate of DNA methylation (DNAm) aging from adolescence to adulthood. DNAm was assayed from blood samples in 381 participants in both adolescence (mean [SD] age= 13.9 [1.6] years) and adulthood (mean [SD] age= 25.9 [2.7] years). Structured diagnostic interviews were completed with participants and their parents at multiple childhood observations (1,950 total) to assess symptoms of common mental health disorders (attention-deficit/hyperactivity disorder, oppositional defiant disorder, conduct disorder, anxiety, and depression) and common types of substance use (alcohol, cannabis, nicotine) and early adversities. Neither childhood mental health symptoms nor substance use variables were associated with DNAm aging cross-sectionally. In contrast, the following mental health symptoms and substance variables were associated with accelerated DNAm aging from adolescence to adulthood: depressive symptoms (b= 0.314, SE= 0.127, p= .014), internalizing symptoms (b= 0.108, SE= 0.049, p= .029), weekly cannabis use (b=1.665, SE= 0.591, p= .005), and years of weekly cannabis use (b= 0.718, SE= 0.283, p= .012). In models testing all individual variables simultaneously, the combined effect of the variables was equivalent to a potential difference of 3.17 to 3.76 years in DNAm aging. A final model tested a variable assessing cumulative exposure to mental health symptoms, substance use, and early adversities. This cumulative variable was strongly associated with accelerated aging (b= 0.126, SE= 0.044, p= .005). Mental health symptoms and substance use accelerated DNAm aging into adulthood in a manner consistent with a shared risk mechanism. Using data from 381 participants in the Great Smoky Mountains Study, the authors examined whether childhood mental health symptoms, substance use, and early adversity accelerate biological aging, as measured by DNA methylation age, from adolescence to adulthood. Depressive symptoms and cannabis use were found to significantly accelerate biological aging. Models that tested the combined effect of mental health symptoms, substance use, and early adversity demonstrated that there was a shared effect across these types of childhood problems on accelerated aging.

DNA repair-deficient premature aging models display accelerated epigenetic age.

Several premature aging mouse models have been developed to study aging and identify interventions that can delay age-related diseases. Yet, it is still unclear whether these models truly recapitulate natural aging. Here, we analyzed DNA methylation in multiple tissues of four previously reported mouse models of premature aging (Ercc1, LAKI, Polg, and Xpg). We estimated DNA methylation (DNAm) age of these samples using the Horvath clock. The most pronounced increase in DNAm age could be observed in Ercc1 mice, a strain which exhibits a deficit in DNA nucleotide excision repair. Similarly, we detected an increase in epigenetic age in fibroblasts isolated from patients with progeroid syndromes associated with mutations in DNA excision repair genes. These findings highlight that mouse models with deficiencies in DNA repair, unlike other premature aging models, display accelerated epigenetic age, suggesting a strong connection between DNA damage and epigenetic dysregulation during aging.

SEX DIFFERENCES IN THE LINK BETWEEN DNA METHYLATION–BASED BIOLOGICAL AGING AND HEALTH IN OLDER INDIVIDUALS

Abstract It is well-established that women live longer than men, however, sex differences in biological aging have not been consistently reported, and may differ depending on the measure used. This study aimed to determine the correlation between DNA methylation (DNAm) age acceleration (AA) measures, with system-wide frailty-index (FI) aging and brain-predicted age difference (brain-PAD), in an initially healthy population of men and women aged ≥70 years. We additionally explored the extent to which these AA measures were associated with clinical measures, and chronic conditions, separately in men and women. DNAm age (Horvath, Hannum, PhenoAge, GrimAge, and DunedinPACE) were estimated in blood from 560 Australians (women, 50.7%) enrolled in the ASPREE study. FI was a deficit accumulation of 67 items including cognition and morbidities. Brain age was estimated from T1-weighted MRI. Clinical measurements, laboratory tests, and self-reports were used to identify chronic illnesses. FI had the strongest correlation with GrimAA and DunedinPACE (range r: 0.20 to 0.24 in both sexes) but was not associated with HorvathAA. Brain-PAD was not correlated with any biological aging measure. Correlations between AA and clinical measures were more commonly found in women than men and were the strongest for DunedinPACE and clinical measures including grip strength, gait speed, and self-rated health (r: -0.23 to 0.24). AA measures, especially GrimAA and DunedinPACE, were significantly associated with hypertension, diabetes, chronic kidney disease in men, and obesity and depression in women. Our findings highlight the importance of considering sex differences when investigating the link between biological age and clinical measures.