Epigenetic age acceleration and cognitive performance over time in older adults.

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

Epigenetic age acceleration and mortality risk prediction in U.S. adults.

Background: Epigenetic clocks have emerged as novel measures of biological age and potential predictors of mortality. We aimed to test whether epigenetic age acceleration (EAA) estimated using different epigenetic clocks predict long-term overall, cardiovascular or cancer mortality. Methods: We analyzed data from 2,105 participants to the 1999-2002 National Health and Nutrition Examination Survey aged ≥50 years old who were followed for mortality through 2019. EAAs was calculated from the residuals of Horvath, Hannum, SkinBlood, Pheno, Zhang, Lin, Weidner, Vidal-Bralo and Grim epigenetic clocks regressed on chronological age. Using cox proportional hazards regression, we estimated the hazard ratio (HR) and 95% confidence interval (CI) for the association of EAA (per 5-year) and the DunedinPoAm pace of aging (per 10% increase) with overall, cardiovascular and cancer mortality, adjusting for covariates and white blood cell composition. Results: During a median follow-up of 17.5 years, 998 deaths occurred, including 272 from cardiovascular disease and 209 from cancer. Overall mortality was most significantly predicted by Grim EAA (P < 0.0001; HR: 1.50, 95% CI: 1.32-1.71) followed by Hannum (P = 0.001; HR: 1.16, 95% CI: 1.07-1.27), Pheno (P = 0.001; HR: 1.13, 95% CI: 1.05-1.21), Horvath (P = 0.007; HR: 1.13, 95% CI: 1.04-1.22) and Vidal-Bralo (P = 0.008; HR: 1.13, 95% CI: 1.03-1.23) EAAs. Grim EAA predicted cardiovascular mortality (P < 0.0001; HR: 1.55, 95% CI: 1.29-1.86), whereas Hannum (P = 0.006; HR: 1.24, 95% CI: 1.07-1.44), Horvath (P = 0.02; HR: 1.18, 95% CI: 1.02-1.35) and Grim (P = 0.049; HR: 1.37, 95% CI: 1.00-1.87) EAAs predicted cancer mortality. DunedinPoAm pace of aging was associated with overall (P = 0.003; HR: 1.23, 95% CI: 1.08-1.38) and cardiovascular (P = 0.04; HR: 1.25, 95% CI: 1.01-1.55) mortality. Conclusions: In a U.S. representative sample, Horvath, Hannum, Pheno, Vidal-Bralo and Grim EAA all predicted overall mortality but only Grim EAA predicted cardiovascular mortality and Horvath, Hannum or Grim EAA predicted cancer mortality. Pace of aging predicted overall and cardiovascular mortality.

Causal associations and shared genetic etiology of neurodegenerative diseases with epigenetic aging and human longevity.

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

Lifestyle differences between co-twins are associated with decreased similarity in their internal and external exposome profiles.

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

Exploring the potential of epigenetic clocks in aging research.

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.

Causal association of epigenetic age acceleration and risk of subacute thyroiditis: a bidirectional Mendelian randomization study.

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

Mendelian randomization analysis reveals the combined effects of epigenetics and telomere biology in hematologic cancers.

BACKGROUND: Telomere shortening and epigenetic modifications are key factors in aging and hematologic diseases. This study investigates the relationship of telomere length and epigenetic age acceleration (EAA) with hematologic cancers, blood cells, and biochemical markers through the epigenetic clocks. METHODS: This study primarily utilizes genome-wide association studies of populations of European descent as instrumental variables, exploring the causal relationships between exposures and outcomes through a bidirectional two-sample Mendelian randomization (MR) approach. MR techniques include inverse variance weighted (IVW), MR Egger, and weighted median modes. Heterogeneity and pleiotropy in MR are assessed using Cochran's Q test and the MR Egger intercept, with the robustness of the conclusions further validated by multivariable MR (MVMR). RESULTS: Our research shows that longer telomere lengths significantly increase the risk of multiple myeloma, leukemia, and lymphoma (OR > 1, P < 0.05) and establish a causal relationship between telomere length and red blood cell indices such as RBC (OR = 1.121, PIVW = 0.034), MCH (OR = 0.801, PIVW = 2.046e-06), MCV (OR = 0.801, PIVW = 0.001), and MCHC (OR = 0.813, PIVW = 0.002). Additionally, MVMR analysis revealed an association between DNA methylation PhenoAge acceleration and alkaline phosphatase (OR = 1.026, PIVW = 0.007). CONCLUSION: The study clarifies the relationships between telomere length, EAA, and hematological malignancies, further emphasizing the prognostic significance of telomere length and EAA. This deepens our understanding of the pathogenesis of hematological diseases, which can inform risk assessment and therapeutic strategies.

Differential white blood cell count and epigenetic clocks: a bidirectional Mendelian randomization study.

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

DNA methylation-estimated phenotypes, telomere length and risk of ischemic stroke: epigenetic age acceleration of screening and a Mendelian randomization study.

BACKGROUND: Aging is a complex biological process that may be accelerated in certain pathological conditions. DNA methylation age (DNAmAge) has emerged as a biomarker for biological age, which can differ from chronological age. This research peels back the layers of the relationship between fast-forward aging and ischemic stroke, poking and prodding the potential two-way causal influences between stroke and biological aging indicators. METHODS: We analyzed a cohort of ischemic stroke patients, comparing DNAmAge with chronological age to measure age acceleration. We assessed variations in age acceleration among stroke subtypes and between sexes. Using Mendelian randomization, we examined the causal links between stroke, aging biomarkers like telomere length, and age acceleration's effect on stroke risk. RESULTS: Our investigation reveals a pronounced association between ischemic stroke and age acceleration, most notably in patients with cardioembolic strokes, who exhibited a striking median difference of 9 years between DNAmAge and chronological age. Furthermore, age acceleration differed significantly across stroke subtypes and was higher in women than in men. In terms of causality, MR analysis indicated a modest negative effect of stroke on telomere length, but no causal effect of age phenotypes on stroke or its subtypes. However, some indication of a potential causal effect of ischemic stroke on PhenoAge acceleration was observed. CONCLUSION: The study provides insight into the relationship between DNAmAge and ischemic stroke, particularly cardioembolic stroke, and suggests possible gender differences. These insights carry profound clinical significance and set stage for future investigations into the entwined pathways of stroke and accelerated aging.

Associations of Epigenetic Age Acceleration With CVD Risks Across the Lifespan: The Bogalusa Heart Study.

Although epigenetic age acceleration (EAA) might serve as a molecular signature of childhood cardiovascular disease (CVD) risk factors and further promote midlife subclinical CVD, few studies have comprehensively examined these life course associations. This study sought to test whether childhood CVD risk factors predict EAA in adulthood and whether EAA mediates the association between childhood CVD risks and midlife subclinical disease. Among 1,580 Bogalusa Heart Study participants, we estimated extrinsic EAA, intrinsic EAA, PhenoAge acceleration (PhenoAgeAccel), and GrimAge acceleration (GrimAgeAccel) during adulthood. We tested prospective associations of longitudinal childhood body mass index (BMI), blood pressure, lipids, and glucose with EAAs using linear mixed effects models. After confirming EAAs with midlife carotid intima-media thickness and carotid plaque, structural equation models examined mediating effects of EAAs on associations of childhood CVD risk factors with subclinical CVD measures. After stringent multiple testing corrections, each SD increase in childhood BMI was significantly associated with 0.6-, 0.9-, and 0.5-year increases in extrinsic EAA, PhenoAgeAccel, and GrimAgeAccel, respectively (P < 0.001 for all 3 associations). Likewise, each SD increase in childhood log-triglycerides was associated with 0.5- and 0.4-year increases in PhenoAgeAccel and GrimAgeAccel (P < 0.001 for both), respectively, whereas each SD increase in childhood high-density lipoprotein cholesterol was associated with a 0.3-year decrease in GrimAgeAccel (P = 0.002). Our findings indicate that PhenoAgeAccel mediates an estimated 27.4% of the association between childhood log-triglycerides and midlife carotid intima-media thickness (P = 0.022). Our data demonstrate that early life CVD risk factors may accelerate biological aging and promote subclinical atherosclerosis.

Causal effects of denture wearing on epigenetic age acceleration and the mediating pathways: a mendelian randomization study.

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

Causal benefits of 25 dietary intakes on epigenetic ageing: a Mendelian randomisation study.

DNA methylation GrimAge acceleration (DMGA) and intrinsic epigenetic age acceleration (IEAA) are important physiological markers for assessing the ageing process. Evidence from cross-sectional studies suggests that some dietary intake is associated with DMGA and IEAA. However, the causal relationship between them has yet to be elucidated. This Mendelian randomisation study uses genetic variants associated with different dietary intakes as instrumental variables to explore the causal benefits of multiple dietary intakes on DMGA and IEAA. Cheese intake, dark chocolate intake, average weekly red wine intake, dried fruit intake, fresh fruit intake, porridge intake, cereal intake, and liver intake had a negative causal association with DMGA, and poultry intake and doughnut intake had a positive causal association with DMGA (p < 0.05). Muesli and bran cereal intake had a negative causal association with IEAA, and pineapple intake had a positive causal association with IEAA (p < 0.05). Dietary intake positively causally associated with IEAA or DMGA may have accelerated biological ageing; conversely, dietary intake negatively causally associated with IEAA or DMGA may have contributed to delaying biological ageing. Based on genetic evidence, this study demonstrated some significant causal benefits of dietary intake on DMGA and IEAA, suggesting the possibility of intervening in DNA methylation acceleration and epigenetic age acceleration by adjusting these food intakes, thereby promoting health and delaying ageing. However, the findings of this study are exploratory and preliminary and need to be supported and validated by evidence from further clinical studies and mechanistic studies.

Effects of walking on epigenetic age acceleration: a Mendelian randomization study.

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

The association between sleep quality and accelerated epigenetic aging with metabolic syndrome in Korean adults.

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

Epigenetic age acceleration and the risk of frailty, and persistent activities of daily living (ADL) disability.

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

DNA methyltransferase 1 (DNMT1) promotes cyst growth and epigenetic age acceleration in autosomal dominant polycystic kidney disease.

Alteration of DNA methylation leads to diverse diseases, and the dynamic changes of DNA methylation (DNAm) on sets of CpG dinucleotides in mammalian genomes are termed "DNAm age" and "epigenetic clocks" that can predict chronological age. However, whether and how dysregulation of DNA methylation promotes cyst progression and epigenetic age acceleration in autosomal dominant polycystic kidney disease (ADPKD) remains elusive. Here, we show that DNA methyltransferase 1 (DNMT1) is upregulated in cystic kidney epithelial cells and tissues and that knockout of Dnmt1 and targeting DNMT1 with hydralazine, a safe demethylating agent, delays cyst growth in Pkd1 mutant kidneys and extends life span of Pkd1 conditional knockout mice. With methyl-CpG binding domain (MBD) protein-enriched genome sequencing (MBD-seq), DNMT1 chromatin immunoprecipitation (ChIP)-sequencing and RNA-sequencing analysis, we identified two novel DNMT1 targets, PTPRM and PTPN22 (members of the protein tyrosine phosphatase family). PTPRM and PTPN22 function as mediators of DNMT1 and the phosphorylation and activation of PKD-associated signaling pathways, including ERK, mTOR and STAT3. With whole-genome bisulfide sequencing in kidneys of patients with ADPKD versus normal individuals, we found that the methylation of epigenetic clock-associated genes was dysregulated, supporting that epigenetic age is accelerated in the kidneys of patients with ADPKD. Furthermore, five epigenetic clock-associated genes, including Hsd17b14, Itpkb, Mbnl1, Rassf5 and Plk2, were identified. Thus, the diverse biological roles of these five genes suggest that their methylation status may not only predict epigenetic age acceleration but also contribute to disease progression in ADPKD.

Signatures of epigenetic, biological and mitotic age acceleration and telomere shortening are associated with arsenic-induced skin lesions.

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

Epigenetic age acceleration is associated with blood lipid levels in a multi-ancestry sample of older U.S. adults.

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