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We investigated whether lifestyle influences epigenetic aging in 143 monozygotic twin pairs discordant for the combined healthy lifestyle score. Twins were scored for four lifestyle factors as unhealthy or healthy; non-smoker, moderate drinker, adequate fruit and vegetable intake, and sufficient physical activity. The combined healthy lifestyle score was calculated for each participant by summing the binary score for each factor. Individual and co-twin analyses were used to assess the relationship between single or combined lifestyle scores, along with DNA methylation age acceleration (AA) calculated using Horvath’s and Li’s epigenetic clocks, focusing on AA and intrinsic epigenetic age acceleration (IEAA) measures. Compared with the twins that scored no or one healthy lifestyle point, those who scored four healthy lifestyle points had lower Li_IEAA with similar results observed in the co-twin analysis. No significant relationships were found in analyses based on Horvath’s clock, although the direction of correlations was consistent with that determined using Li’s clock. Smoking and drinking did not significantly affect DNA methylation AA; however, physical activity and intake of vegetables and fruits did, although the influence varied depending on the epigenetic clock. Our findings suggest that a healthy lifestyle may be an important way to delay aging and prevent age-related diseases.

Background Accelerated epigenetic age has been proposed as a biomarker of increased aging, which may indicate disruptions in cellular and organ system homeostasis and thus contribute to sensitivity to environmental exposures. Methods Using 497 participants from the CATHGEN cohort, we evaluated whether accelerated epigenetic aging increases cardiovascular sensitivity to traffic-related air pollution (TRAP) exposure. We used residential proximity to major roadways and source apportioned air pollution models as measures of TRAP exposure, and chose peripheral arterial disease (PAD) and blood pressure as outcomes based on previous associations with TRAP. We used Horvath epigenetic age acceleration (AAD) and phenotypic age acceleration (PhenoAAD) as measures of age acceleration, and adjusted all models for chronological age, race, sex, smoking, and socioeconomic status. Results We observed significant interactions between TRAP and both AAD and PhenoAAD. Interactions indicated that increased epigenetic age acceleration elevated associations between proximity to roadways and PAD. Interactions were also observed between AAD and gasoline and diesel source apportioned PM2.5. Conclusion Epigenetic age acceleration may be a biomarker of sensitivity to air pollution, particularly for TRAP in urban cohorts. This presents a novel means by which to understand sensitivity to air pollution and provides a molecular measure of environmental sensitivity.

Lung function, strongly associated with morbidity and mortality, decreases with age. This study examines whether poor adult lung function is associated with age accelerations (AAs). DNA methylation (DNAm) based AAs, lifespan predictors (GrimAge and plasminogen activator inhibitor 1-PAI1) and their related age-adjusted measures were estimated from peripheral blood at two time points (8-to-11 years apart) in adults from two cohorts: SAPALDIA (n=987) and ECRHS (n=509). Within each cohort and stratified by gender (except for estimators from GrimAge and PAI1), AAs were used as predictors in multivariate linear regression with cross-sectional lung function parameters, and in covariate-adjusted mixed linear regression with longitudinal change in lung function and meta-analysed. AAs were found cross-sectionally associated with lower mean FEV1 (Forced Expiratory Volume in one second) (AA-residuals:P-value=4x10-4; Intrinsic Epigenetic AA:P-value=2x10-4) in females at the follow-up time point only, and the same trend was observed for FVC (Forced Vital Capacity). Both lifespan and plasma level predictors were observed strongly associated with lung function decline and the decline was stronger in the follow-up time points (strongest association between FEV1 and DNAmAge GrimAge:P-value=1.25x10-17). This study suggests that DNAm based lifespan and plasma level predictors can be utilised as important factors to assess lung health in adults. publishedVersion

Alterations in global DNA methylation play a critical role in both aging and cancer, and DNA methylation (DNAm) age drift has been implicated in cancer risk and pathogenesis. In the present study, we analyzed the TCGA cohort of papillary and follicular thyroid carcinoma (PTC and FTC) for their DNAm age and association with clinic-pathological features. In 54 noncancerous thyroid (NT) samples, DNAm age was highly correlated with patient chronological age (R2 = 0.928, p = 2.6 × 10−31), but drifted to younger than chronological age in most specimens, especially those from patients &gt, 50 years old. DNAm age in 502 tumors was also correlated with patient chronological age, but to a much lesser extent (R2 = 0.403). Highly drifted DNAm age (HDDA) was identified in 161 tumors, among which were 101 with DNAm age acceleration while 60 with DNAm age deceleration. Tumors with HDDA were characterized by the robust aberrations in metabolic activities, extracellular microenvironment components and inflammation/immunology responses, and dedifferentiation. Importantly, HDDA in tumors independently predicted shorter disease-free survival of patients. Collectively, NT thyroids from TC patients have younger DNAm age, while HDDA frequently occurs in TCs, and contributes to the TC progression and poor patient outcomes. HDDA may serve as a new prognostic factor for TCs.

Aging is the predominant risk factor for most degenerative diseases, including chronic obstructive pulmonary disease (COPD). This process is however very heterogeneous. Defining the biological aging of individual tissues may contribute to better assess this risky process. In this study, we examined the biological age of induced sputum (IS) cells, and peripheral blood leukocytes in the same subject, and compared these to assess whether biological aging of blood leukocytes mirrors that of IS cells. Biological aging was assessed in 18 COPD patients (72.4 ± 7.7 years; 50% males). We explored mitotic and non-mitotic aging pathways, using telomere length (TL) and DNA methylation-based age prediction (DNAmAge) and age acceleration (AgeAcc) (i.e., difference between DNAmAge and chronological age). Data on demographics, life style and occupational exposure, lung function, and clinical and blood parameters were collected. DNAmAge (67.4 ± 5.80 vs. 61.6 ± 5.40 years; p = 0.0003), AgeAcc (−4.5 ± 5.02 vs. −10.8 ± 3.50 years; p = 0.0003), and TL attrition (1.05 ± 0.35 vs. 1.48 ± 0.21 T/S; p = 0.0341) are higher in IS cells than in blood leukocytes in the same patients. Blood leukocytes DNAmAge (r = 0.927245; p = 0.0026) and AgeAcc (r = 0.916445; p = 0.0037), but not TL, highly correlate with that of IS cells. Multiple regression analysis shows that both blood leukocytes DNAmAge and AgeAcc decrease (i.e., younger) in patients with FEV1% enhancement (p = 0.0254 and p = 0.0296) and combined inhaled corticosteroid (ICS) therapy (p = 0.0494 and p = 0.0553). In conclusion, new findings from our work reveal a differential aging in the context of COPD, by a direct quantitative comparison of cell aging in the airway with that in the more accessible peripheral blood leukocytes, providing additional knowledge which could offer a potential translation into the disease management.

Advanced age increases risk for cancer, cardiovascular disease, and all-cause mortality. However, people do not age at the same rate, and biological age (frequently measured through DNA methylation) can be older than chronological age. Environmental factors have been associated with the rate of biological aging, but it is not known whether persistent endocrine-disrupting compounds (EDCs) like polybrominated biphenyl (PBB) would associate with age acceleration. Three different epigenetic age acceleration measures (intrinsic, extrinsic, and phenotypic) were calculated from existing epigenetic data in whole blood from a population highly exposed to PBB (N=658). Association between serum PBB concentration and these measures was tested, controlling for sex, lipid levels, and estimated cell type proportions. Higher PBB levels associated with increased age acceleration (intrinsic: β=0.24, 95%CI=0.01-0.46, p = 0.03; extrinsic: β=0.39, 95%CI=0.12-0.65, p = 0.004; and phenotypic: β=0.30, 95%CI=0.05-0.54, p = 0.01). Neither age when exposed to PBB nor sex statistically interacted with PBB to predict age acceleration, but, in stratified analyses, the association between PBB and age acceleration was only in people exposed before finishing puberty and in men. This suggests that EDCs can associate with the biological aging process, and further studies are warranted to investigate other environmental pollutants’ effect on aging.

Background: Abnormal DNA methylation (DNAm) age has been assumed to be an indicator for canceration and all-cause mortality. However, associations between DNAm age and molecular features of stomach adenocarcinoma (STAD), and its prognosis have not been systematically studied.Method: We calculated the DNAm age of 591 STAD samples and 115 normal stomach samples from The Cancer Genome Atlas (TCGA) and gene expression omnibus (GEO) database using the Horvath’s clock model. Meanwhile, we utilized survival analysis to evaluate the prognostic value of DNAm age and epigenetic age acceleration shift. In addition, we performed weighted gene co-expression network analysis (WGCNA) to identify DNAm age-associated gene modules and pathways. Finally, the association between DNAm age and molecular features was performed by correlation analysis.Results: DNA methylation age was significantly correlated with chronological age in normal gastric tissues (r = 0.85, p < 0.0001), but it was not associated with chronological age in STAD samples (r = 0.060, p = 0.2369). Compared with tumor adjacent normal tissue, the DNAm age of STAD tissues was significantly decreased. Meanwhile, chronological age in STAD samples was higher than its DNAm age. Both DNAm age and epigenetic acceleration shift were associated with the prognosis of STAD patients. By using correlation analysis, we also found that DNAm age was associated with immunoactivation and stemness in STAD samples.Conclusion: In summary, epigenetic age acceleration of STAD was associated with tumor stemness, immunoactivation, and favorable prognosis.

Background: The blood metabolome incorporates cues from the environment and the host’s genetic background, potentially offering a holistic view of an individual’s health status. Methods: We have compiled a vast resource of proton nuclear magnetic resonance metabolomics and phenotypic data encompassing over 25 000 samples derived from 26 community and hospital-based cohorts. Results: Using this resource, we constructed a metabolomics-based age predictor (metaboAge) to calculate an individual’s biological age. Exploration in independent cohorts demonstrates that being judged older by one’s metabolome, as compared with one’s chronological age, confers an increased risk on future cardiovascular disease, mortality, and functionality in older individuals. A web-based tool for calculating metaboAge ( metaboage.researchlumc.nl ) allows easy incorporation in other epidemiological studies. Access to data can be requested at bbmri.nl/samples-images-data . Conclusions: In summary, we present a vast resource of metabolomics data and illustrate its merit by constructing a metabolomics-based score for biological age that captures aspects of current and future cardiometabolic health.

Chronic obstructive pulmonary disease (COPD) is a frequent diagnosis in older individuals and contributor to global morbidity and mortality. Given the link between lung disease and aging, we need to understand how molecular indicators of aging relate to lung function and disease. Using data from the population-based KORA (Cooperative Health Research in the Region of Augsburg) surveys, we associated baseline epigenetic (DNA methylation) age acceleration with incident COPD and lung function. Models were adjusted for age, sex, smoking, height, weight, and baseline lung disease as appropriate. Associations were replicated in the Normative Aging Study. Of 770 KORA participants, 131 developed incident COPD over 7 years. Baseline accelerated epigenetic aging was significantly associated with incident COPD. The change in age acceleration (follow-up - baseline) was more strongly associated with COPD than baseline aging alone. The association between the change in age acceleration between baseline and follow-up and incident COPD replicated in the Normative Aging Study. Associations with spirometric lung function parameters were weaker than those with COPD, but a meta-analysis of both cohorts provide suggestive evidence of associations. Accelerated epigenetic aging, both baseline measures and changes over time, may be a risk factor for COPD and reduced lung function.

Methylation levels measured at defined sites across the genome have recently been shown to be correlated with an individual’s chronological age. Age acceleration, or the difference between age estimated from DNA methylation status and chronological age, has been proposed as a novel biomarker of aging. In this study, the cross-sectional association between two different measures of age acceleration and cognitive function was investigated using whole blood samples from 2,157 African American participants 47–70 years of age in the population-based Atherosclerosis Risk in Communities (ARIC) Study. Cognition was evaluated using three domain-specific tests. A significant inverse association between a 1-year increase in age acceleration calculated using a blood-based age predictor and scores on the Word Fluency Test was found using a general linear model adjusted for chronological age, gender, and years of education (β = −0.140 words; p = .001) and after adding other potential confounding variables (β = −0.104 words, p = .023). The results were replicated in 1,670 European participants in the Generation Scotland: Scottish Family Health Study (fully adjusted model: β = −0.199 words; p = .034). A significant association was also identified in a trans-ethnic meta-analysis across cohorts that included an additional 708 European American ARIC study participants (fully adjusted model: β = −0.110 words, p = .003). There were no associations found using an estimate of age acceleration derived from multiple tissues. These findings provide evidence that age acceleration is a correlate of performance on a test of verbal fluency in middle-aged adults.

Background Many CpGs become hyper or hypo-methylated with age. Multiple methods have been developed by Horvath et al. to estimate DNA methylation (DNAm) age including Pan-tissue, Skin & Blood, PhenoAge, and GrimAge. Pan-tissue and Skin & Blood try to estimate chronological age in the normal population whereas PhenoAge and GrimAge use surrogate markers associated with mortality to estimate biological age and its departure from chronological age. Here, we applied Horvath’s four methods to calculate and compare DNAm age in 499 subjects with type 1 diabetes (T1D) from the Diabetes Control and Complications Trial/Epidemiology of Diabetes Interventions and Complications (DCCT/EDIC) study using DNAm data measured by Illumina EPIC array in the whole blood. Association of the four DNAm ages with development of diabetic complications including cardiovascular diseases (CVD), nephropathy, retinopathy, and neuropathy, and their risk factors were investigated. Results Pan-tissue and GrimAge were higher whereas Skin & Blood and PhenoAge were lower than chronological age (p < 0.0001). DNAm age was not associated with the risk of CVD or retinopathy over 18–20 years after DNAm measurement. However, higher PhenoAge (β = 0.023, p = 0.007) and GrimAge (β = 0.029, p = 0.002) were associated with higher albumin excretion rate (AER), an indicator of diabetic renal disease, measured over time. GrimAge was also associated with development of both diabetic peripheral neuropathy (OR = 1.07, p = 9.24E−3) and cardiovascular autonomic neuropathy (OR = 1.06, p = 0.011). Both HbA1c (β = 0.38, p = 0.026) and T1D duration (β = 0.01, p = 0.043) were associated with higher PhenoAge. Employment (β = − 1.99, p = 0.045) and leisure time (β = − 0.81, p = 0.022) physical activity were associated with lower Pan-tissue and Skin & Blood, respectively. BMI (β = 0.09, p = 0.048) and current smoking (β = 7.13, p = 9.03E−50) were positively associated with Skin & Blood and GrimAge, respectively. Blood pressure, lipid levels, pulse rate, and alcohol consumption were not associated with DNAm age regardless of the method used. Conclusions Various methods of measuring DNAm age are sub-optimal in detecting people at higher risk of developing diabetic complications although some work better than the others.

Highlights • In young adult women, slower epigenetic clock predicted less symptoms of anxiety. • In young adult women, slower epigenetic clock predicted greater cortical GM volume. • This effect of epigenetic clock in young adult women was largest in frontal lobe. • The link of epigenetic clock and anxiety was mediated by GM volume in frontal lobe. • No similar relationships were found in young adult men or adolescents., DNA methylation changes consistently throughout life and age-dependent alterations in DNA methylation can be used to estimate one’s epigenetic age. Post-mortem studies revealed higher epigenetic age in brains of patients with major depressive disorder, as compared with controls. Since MDD is highly correlated with anxiety, we hypothesized that symptoms of anxiety, as well as lower volume of grey matter (GM) in depression-related cortical regions, will be associated with faster epigenetic clock in a community-based sample of young adults. Participants included 88 young adults (53% men; 23–24 years of age) from the European Longitudinal Study of Pregnancy and Childhood (ELSPAC) who participated in its neuroimaging follow-up and provided saliva samples for epigenetic analysis. Epigenetic age was calculated according to Horvath (Horvath, 2013). Women had slower epigenetic clock than men (Cohen’s d = 0.48). In women (but not men), slower epigenetic clock was associated with less symptoms of anxiety. In the brain, women (but not men) with slower epigenetic clock had greater GM volume in the cerebral cortex (brain size-corrected; R2 = 0.07). Lobe-specific analyses showed that in women (but not men), slower epigenetic clock was associated with greater GM volume in frontal lobe (R2 = 0.16), and that GM volume in frontal lobe mediated the relationship between the speed of epigenetic clock and anxiety trait (ab = 0.15, SE = 0.15, 95% CI [0.007; 0.369]). These findings were not replicated, however, in a community-based sample of adolescents (n = 129; 49% men; 12–19 years of age), possibly due to the different method of tissue collection (blood vs. saliva) or additional sources of variability in the cohort of adolescents (puberty stages, socioeconomic status, prenatal exposure to maternal smoking during pregnancy).

The discrepancy of DNA methylation age (DNAmAge) with chronological age (termed as age acceleration, AA) has been identified to be associated with many aging-related health outcomes including hypertension. Since taking antihypertensive medication (AHM) could prevent aging-related diseases caused by hypertension, we hypothesized that using AHM could also reduce the AA. We examined this hypothesis among 546 males aged 55-85 years by exploring the associations of AHM use with AA and its change rate (ΔAA) in two visits with a median follow-up of 3.86 years. Horvath DNAmAge was derived from DNA methylation profiles measured by Illumina HumanMethylation450 BeadChip and information on AHM use was collected by physician interview. A general decreasing pattern of AA was observed between the two visits. After the fully adjusting for potential covariates including hypertension, any AHM use showed a cross-sectional significant association with higher AA at each visit, as well as a longitudinal association with increased ΔAA between visits. Particularly, relative to participants who never took any AHM, individuals with continuous AHM use had a higher ΔAA of 0.6 year/chronological year. This finding underlines that DNAmAge and AA may not be able to capture the preventive effects of AHMs that reduce cardiovascular risks and mortality.

Background: Helicobacter pylori (HP) infection and chronic atrophic gastritis (CAG) have shown strong associations with the development of gastric cancer. This study aimed to examine whether both risk factors are associated with accelerated epigenetic ageing, as determined by the ‘DNA methylation age’, in a population-based study of older adults (n=1477). Methods: Serological measurements of HP antibodies and pepsinogen I and II for CAG definition were obtained by ELISA kits. Whole blood DNA methylation profiles were measured by Illumina Human Methylation450K Beadchip. DNA methylation ages were calculated by two algorithms proposed by Horvath and Hannum et al. Results: After adjusting for potential covariates in linear regression models, we found that HP infection, infection with virulent HP strains (CagA+) and severe CAG were significantly associated with an increase in DNA methylation age by ∼0.4, 0.6 and 1 year (all P-values

The repeat expansion in C9orf72 is the most common cause of amyotrophic lateral sclerosis and frontotemporal dementia. C9orf72 patients present with a wide range in disease duration and age of onset. The strongest risk factor for both syndromes is aging, which was linked to DNA methylation (DNAm) age based on the cumulative assessment of the methylation levels of 353 CpGs included on the genome-wide 450k BeadChip. DNAm age may reflect biological age better than chronological age. We conducted a genome-wide blood DNA methylation study of 46 unrelated C9orf72 patients. After correction for multiple testing, none of the CpGs demonstrated association between its methylation level and disease duration or age of onset. However, we detected a significant reverse correlation of DNAm age-acceleration with disease duration and age of onset, suggesting that for every 5-year increase in DNAm age-acceleration there is a 3.2-year earlier age of onset and 1.5-year shorter disease duration. The significant correlations remain after adjusting for gender, TMEM106B genotypes, disease phenotype and C9orf72 5′CpG island methylation status. A similar trend was observed for the blood DNA of affected members of an extended C9orf72 family; and tissues from the central nervous system of C9orf72 autopsy cases. For instance, regression analysis suggested that a 5-year increase in DNAm age-acceleration is linked to an earlier age of onset by 4.7 or 5.5 years for frontal cortex or spinal cord, respectively. Blood DNAm age may be a useful biomarker for biological age, because blood DNAm age-acceleration was similar to all investigated brain tissues, except for cerebellum that ages more slowly. In conclusion, DNA methylation analysis of C9orf72 patients revealed that increased DNAm age-acceleration is associated with a more severe disease phenotype with a shorter disease duration and earlier age of onset. Electronic supplementary material The online version of this article (doi:10.1007/s00401-017-1713-y) contains supplementary material, which is available to authorized users.

Epigenetic age estimations based on DNA methylation (DNAm) can predict human chronological age with a high level of accuracy. These DNAm age algorithms can also be used to index advanced cellular age, when estimated DNAm age exceeds chronological age. Advanced DNAm age has been associated with several diseases and metabolic and inflammatory pathology, but the causal direction of this association is unclear. The goal of this study was to examine potential bidirectional associations between advanced epigenetic age and metabolic and inflammatory markers over time in a longitudinal cohort of 179 veterans with a high prevalence of posttraumatic stress disorder (PTSD) who were assessed over the course of two years. Analyses focused on two commonly investigated metrics of advanced DNAm age derived from the Horvath (developed across multiple tissue types) and Hannum (developed in whole blood) DNAm age algorithms. Results of cross-lagged panel models revealed that advanced Hannum DNAm age at Time 1 (T1) was associated with increased (i.e., accounting for T1 levels) metabolic syndrome (MetS) severity at Time 2 (T2; p = < 0.001). This association was specific to worsening lipid panels and indicators of abdominal obesity ( p = 0.001). In contrast, no baseline measures of inflammation or metabolic pathology were associated with changes in advanced epigenetic age over time. No associations emerged between advanced Horvath DNAm age and any of the examined biological parameters. Results suggest that advanced epigenetic age, when measured using an algorithm developed in whole blood, may be a prognostic marker of pathological metabolic processes. This carries implications for understanding pathways linking advanced epigenetic age to morbidity and mortality.

DNA methylation (DNAm) is an emerging estimator of biological aging, i.e., the often-defined &ldquo, epigenetic clock&rdquo, with a unique accuracy for chronological age estimation (DNAmAge). In this pilot longitudinal study, we examine the hypothesis that intensive relaxing training of 60 days in patients after myocardial infarction and in healthy subjects may influence leucocyte DNAmAge by turning back the epigenetic clock. Moreover, we compare DNAmAge with another mechanism of biological age, leucocyte telomere length (LTL) and telomerase. DNAmAge is reduced after training in healthy subjects (p = 0.053), but not in patients. LTL is preserved after intervention in healthy subjects, while it continues to decrease in patients (p = 0.051). The conventional negative correlation between LTL and chronological age becomes positive after training in both patients (p &lt, 0.01) and healthy subjects (p &lt, 0.05). In our subjects, DNAmAge is not associated with LTL. Our findings would suggest that intensive relaxing practices influence different aging molecular mechanisms, i.e., DNAmAge and LTL, with a rejuvenating effect. Our study reveals that DNAmAge may represent an accurate tool to measure the effectiveness of lifestyle-based interventions in the prevention of age-related diseases.

Background Psoriasis (Ps) is a common chronic inflammatory skin disease. The keratinocytes of psoriatic skin defy normal apoptosis and exhibit active cell proliferation. Aberrant DNA methylation (DNAm) has been suggested relevant through regulating the expression of Ps susceptibility genes. However, it is unclear whether the biological age inferred from DNA methylome is affected. Results To address the above issue, we applied a recently developed methylation clock model to our Chinese Han population dataset, which includes DNAm data of 114 involved psoriatic skin tissues (PP) and 41 uninvolved psoriatic skin tissues (PN) from Ps patients, and 62 normal skin tissues (NN) from health controls. We first confirmed the applicability of the clock in PN and NN. We then showed that PP samples have largely unchanged DNAm age, and that no association was observed between available clinical features and DNAm age acceleration. Examination of genome-wide CpGs yielded age-associated CpGs with concordant age-association coefficients among the three groups, which was also supported by an external dataset. We also interestingly observed two clock CpGs differentially methylated between PP and PN. Conclusions Overall, our results suggest no significant alteration in DNAm age in PN and PP. Therefore, the increase in keratinocyte proliferation and alteration in DNAm caused by Ps may not affect the biological age of psoriatic skin tissue. Electronic supplementary material The online version of this article (10.1186/s13148-018-0584-y) contains supplementary material, which is available to authorized users.

Epigenetic clocks for mice were generated based on deep-sequencing analysis of the methylome. Here, we demonstrate that site-specific analysis of DNA methylation levels by pyrosequencing at only three CG dinucleotides (CpGs) in the genes Prima1, Hsf4, and Kcns1 facilitates precise estimation of chronological age in murine blood samples, too. DBA/2 mice revealed accelerated epigenetic aging as compared to C57BL6 mice, which is in line with their shorter life-expectancy. The three-CpG-predictor provides a simple and cost-effective biomarker to determine biological age in large intervention studies with mice.

Background DNA methylation (DNAm) age was found to be an indicator for all-cause mortality, cancer incidence, and longevity, but no study has involved in the associations of DNAm age with the prognosis of breast cancer. Methods We retrieved information of 1076 breast cancer patients from Genomic Data Commons (GDC) data portal on March 30, 2017, including breast cancer DNAm profiling, demographic features, clinicopathological parameters, recurrence, and all-cause fatality. Horvath’s method was applied to calculate the DNAm age. Cox proportional hazards regression models were used to test the associations between DNAm age of the cancerous tissues and the prognosis (recurrence of breast cancer and all-cause fatality) with or without adjusting for chronological age and clinicopathological parameters. Results The DNAm age was markedly decelerated in the patients who were premenopausal, ER or PR negative, HER2-enriched or basal-like than their counterparts. In the first five-year follow-up dataset for survival, every ten-year increase in DNAm age was associated with a 15% decrease in fatality; subjects with DNAm age in the second (HR: 0.52; 95%CI: 0.29–0.92), the third (HR: 0.49; 95%CI: 0.27–0.87) and the fourth quartile (HR: 0.38; 95%CI: 0.20–0.72) had significant longer survival time than those in the first quartile. In the first five-year follow-up dataset for recurrence, every ten-year increase in DNAm age was associated with a 14% decrease of the recurrence; in the categorical analysis, a clear dose-response was shown (P for trend =0.02) and the fourth quartile was associated with a longer recurrence free survival (HR: 0.32; 95%CI: 0.14–0.74). In the full follow-up dataset, similar results were obtained. Conclusions DNAm age of breast cancer tissue, which associated with menopausal status and pathological features, was a strong independent predictor of the prognosis. It was suggested that the prognosis of breast cancer was related to intrinsic biological changes and specific molecular targets for treatment of breast cancer may be implicit.

ObjectivesOur aim was to investigate the association of epigenetic age and physical capability in later life. Having a higher epigenetic than chronological age (known as age acceleration (AA)) has been found to be associated with an increased rate of mortality. Similarly, physical capability has been proposed as a marker of ageing due to its consistent associations with mortality.SettingThe MRC National Survey of Health and Development (NSHD) cohort study.ParticipantsWe used data from 790 women from the NSHD who had DNA methylation data available.DesignEpigenetic age was calculated using buccal cell (n=790) and matched blood tissue (n=152) from 790 female NSHD participants. We investigated the association of AA at age 53 with changes in physical capability in women from ages 53 to 60–64. Regression models of change in each measure of physical capability on AA were conducted. Secondary analysis focused on the relationship between AA and smoking, alcohol, body mass index (BMI) and socioeconomic position.Outcome measuresThree objective measures of physical capability were used: grip strength, standing balance time and chair rise speed.ResultsEpigenetic age was lower than chronological age (mean 53.4) for both blood (50.3) and buccal cells (42.8). AA from blood was associated with a greater decrease in grip strength from ages 53 to 60–64 (0.42 kg decrease per year of AA, 95% CI 0.03, 0.82 kg; p=0.03, n=152), but no associations were observed with standing balance time or chair rise speed. Current smoking and lower BMI were associated with lower epigenetic age from buccal cells.ConclusionsWe found evidence that AA in blood is associated with a greater decrease in grip strength in British females aged between 53 and 60–64, but no association with standing balance time or chair rise speed was found.

Background Previous studies have developed models predicting methylation age from DNA methylation in blood and other tissues (epigenetic clock) and suggested the difference between DNA methylation and chronological ages as a marker of healthy aging. The goal of this study was to confirm and expand such observations by investigating whether different concepts of the epigenetic clocks in a population-based cohort are associated with cancer, cardiovascular, and all-cause mortality. Results DNA methylation age was estimated in a cohort of 1863 older people, and the difference between age predicted by DNA methylation and chronological age (Δage) was calculated. A case-cohort design and weighted proportional Cox hazard models were used to estimate associations of Δage with cancer, cardiovascular, and all-cause mortality. Hazard ratios for Δage (per 5 years) calculated using the epigenetic clock developed by Horvath were 1.23 (95 % CI 1.10–1.38) for all-cause mortality, 1.22 (95 % CI 1.03–1.45) for cancer mortality, and 1.19 (95 % CI 0.98–1.43) for cardiovascular mortality after adjustment for batch effects, age, sex, educational level, history of chronic diseases, hypertension, smoking status, body mass index, and leucocyte distribution. Associations were similar but weaker for Δage calculated using the epigenetic clock developed by Hannum. Conclusions These results show that age acceleration in terms of the difference between age predicted by DNA methylation and chronological age is an independent predictor of all-cause and cause-specific mortality and may be useful as a general marker of healthy aging. Electronic supplementary material The online version of this article (doi:10.1186/s13148-016-0228-z) contains supplementary material, which is available to authorized users.

Background: Ambient particles have been shown to exacerbate measures of biological aging; yet, no studies have examined their relationships with DNA methylation age (DNAm-age), an epigenome-wide DNA methylation based predictor of chronological age. Objective: We examined the relationship of DNAm-age with fine particulate matter (PM2.5), a measure of total inhalable particle mass, and black carbon (BC), a measure of particles from vehicular traffic. Methods: We used validated spatiotemporal models to generate 1-year PM2.5 and BC exposure levels at the addresses of 589 older men participating in the VA Normative Aging Study with 1–3 visits between 2000 and 2011 ( n = 1032 observations). Blood DNAm-age was calculated using 353 CpG sites from the Illumina HumanMethylation450 BeadChip. We estimated associations of PM2.5 and BC with DNAm-age using linear mixed effects models adjusted for age, lifestyle/environmental factors, and aging-related diseases. Results: After adjusting for covariates, a 1-μg/m3 increase in PM2.5 (95% CI: 0.30, 0.75, P < 0.0001) was significantly associated with a 0.52-year increase in DNAm-age. Adjusted BC models showed similar patterns of association (β = 3.02, 95% CI: 0.48, 5.57, P = 0.02). Only PM2.5 (β = 0.54, 95% CI: 0.24, 0.84, P = 0.0004) remained significantly associated with DNAm-age in two-particle models. Methylation levels from 20 of the 353 CpGs contributing to DNAm-age were significantly associated with PM2.5 levels in our two-particle models. Several of these CpGs mapped to genes implicated in lung pathologies including LZTFL1 , PDLIM5 , and ATPAF1 . Conclusion: Our results support an association of long-term ambient particle levels with DNAm-age and suggest that DNAm-age is a biomarker of particle-related physiological processes.