In utero exposure to the Great Depression is reflected in late-life epigenetic aging signatures.

Research on maternal-fetal epigenetic programming argues that adverse exposures to the intrauterine environment can have long-term effects on adult morbidity and mortality. However, causal research on epigenetic programming in humans at a population level is rare and is often unable to separate intrauterine effects from conditions in the postnatal period that may continue to impact child development. In this study, we used a quasi-natural experiment that leverages state-year variation in economic shocks during the Great Depression to examine the causal effect of environmental exposures in early life on late-life accelerated epigenetic aging for 832 participants in the US Health and Retirement Study (HRS). HRS is the first population-representative study to collect epigenome-wide DNA methylation data that has the sample size and geographic variation necessary to exploit quasi-random variation in state environments, which expands possibilities for causal research in epigenetics. Our findings suggest that exposure to changing economic conditions in the 1930s had lasting impacts on next-generation epigenetic aging signatures that were developed to predict mortality risk (GrimAge) and physiological decline (DunedinPoAm). We show that these effects are localized to the in utero period specifically as opposed to the preconception, postnatal, childhood, or early adolescent periods. After evaluating endogenous shifts in mortality and fertility related to Depression-era birth cohorts, we conclude that these effects likely represent lower bound estimates of the true impacts of the economic shock on long-term epigenetic aging.

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

BACKGROUND: The relationship between accelerated epigenetic aging and musculoskeletal outcomes in women with HIV (WWH) has not been studied. METHODS: 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. RESULTS: 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. CONCLUSIONS: Accelerated epigenetic aging was observed in WWH as compared with women without HIV and was associated with lower physical function in both groups.

A perspective on epigenomic aging processes in the human brain and their plasticity in patients with mental disorders - a systematic review.

The debate surrounding nature versus nurture remains a central question in neuroscience, psychology, and in psychiatry, holding implications for both aging processes and the etiology of mental illness. Epigenetics can serve as a bridge between genetic predisposition and environmental influences, thus offering a potential avenue for addressing these questions. Epigenetic clocks, in particular, offer a theoretical framework for measuring biological age based on DNA methylation signatures, enabling the identification of disparities between biological and chronological age. This structured review seeks to consolidate current knowledge regarding the relationship between mental disorders and epigenetic age within the brain. Through a comprehensive literature search encompassing databases such as EBSCO, PubMed, and ClinicalTrials.gov, relevant studies were identified and analyzed. Studies that met inclusion criteria were scrutinized, focusing on those with large sample sizes, analyses of both brain tissue and blood samples, investigation of frontal cortex markers, and a specific emphasis on schizophrenia and depressive disorders. Our review revealed a paucity of significant findings, yet notable insights emerged from studies meeting specific criteria. Studies characterized by extensive sample sizes, analysis of brain tissue and blood samples, assessment of frontal cortex markers, and a focus on schizophrenia and depressive disorders yielded particularly noteworthy results. Despite the limited number of significant findings, these studies shed light on the complex interplay between epigenetic aging and mental illness. While the current body of literature on epigenetic aging in mental disorders presents limited significant findings, it underscores the importance of further research in this area. Future studies should prioritize large sample sizes, comprehensive analyses of brain tissue and blood samples, exploration of specific brain regions such as the frontal cortex, and a focus on key mental disorders. Such endeavors will contribute to a deeper understanding of the relationship between epigenetic aging and mental illness, potentially informing novel diagnostic and therapeutic approaches.

Epigenetic Aging Helps Explain Differential Resilience in Older Adults.

Past research suggests that resilience to health hazards increases with age, potentially because less resilient individuals die at earlier ages, leaving behind their more resilient peers. Using lifetime cigarette smoking as a model health hazard, we examined whether accelerated epigenetic aging (indicating differences in the speed of individuals' underlying aging process) helps explain age-related resilience in a nationally representative sample of 3,783 older U.S. adults from the Health and Retirement Study. Results of mediation moderation analyses indicated that participants aged 86 or older showed a weaker association between lifetime cigarette smoking and mortality relative to participants aged 76-85 and a weaker association between smoking and multimorbidity relative to all younger cohorts. This moderation effect was mediated by a reduced association between smoking pack-years and epigenetic aging. This research helps identify subpopulations of particularly resilient individuals and identifies epigenetic aging as a potential mechanism explaining this process. Interventions in younger adults could utilize epigenetic aging estimates to identify the most vulnerable individuals and intervene before adverse health outcomes, such as chronic disease morbidity or mortality, manifest.

Childhood adversity, accelerated GrimAge, and associated health consequences.

Childhood adversity is linked to psychological, behavioral, and physical health problems, including obesity and cardiometabolic disease. Epigenetic alterations are one pathway through which the effects of early life stress and adversity might persist into adulthood. Epigenetic mechanisms have also been proposed to explain why cardiometabolic health can vary greatly between individuals with similar Body Mass Index (BMIs). We evaluated two independent cross-sectional cohorts of adults without known medical illness, one of which explicitly recruited individuals with early life stress (ELS) and control participants (n = 195), and the other a general community sample (n = 477). In these cohorts, we examine associations between childhood adversity, epigenetic aging, and metabolic health. Childhood adversity was associated with increased GrimAge Acceleration (GAA) in both cohorts, both utilizing a dichotomous yes/no classification (both p < 0.01) as well as a continuous measure using the Childhood Trauma Questionnaire (CTQ) (both p < 0.05). Further investigation demonstrated that CTQ subscales for physical and sexual abuse (both p < 0.05) were associated with increased GAA in both cohorts, whereas physical and emotional neglect were not. In both cohorts, higher CTQ was also associated with higher BMI and increased insulin resistance (both p < 0.05). Finally, we demonstrate a moderating effect of BMI on the relationship between GAA and insulin resistance where GAA correlated with insulin resistance specifically at higher BMIs. These results, which were largely replicated between two independent cohorts, suggest that interactions between epigenetics, obesity, and metabolic health may be important mechanisms through which childhood adversity contributes to long-term physical and metabolic health effects.

Adaptive predictor-set linear model: An imputation-free method for linear regression prediction on data sets with missing values.

Linear regression (LR) is vastly used in data analysis for continuous outcomes in biomedicine and epidemiology. Despite its popularity, LR is incompatible with missing data, which frequently occur in health sciences. For parameter estimation, this shortcoming is usually resolved by complete-case analysis or imputation. Both work-arounds, however, are inadequate for prediction, since they either fail to predict on incomplete records or ignore missingness-induced reduction in prediction accuracy and rely on (unrealistic) assumptions about the missing mechanism. Here, we derive adaptive predictor-set linear model (aps-lm), capable of making predictions for incomplete data without the need for imputation. It is derived by using a predictor-selection operation, the Moore-Penrose pseudoinverse, and the reduced QR decomposition. aps-lm is an LR generalization that inherently handles missing values. It is applied on a reference data set, where complete predictors and outcome are available, and yields a set of privacy-preserving parameters. In a second stage, these are shared for making predictions of the outcome on external data sets with missing entries for predictors without imputation. Moreover, aps-lm computes prediction errors that account for the pattern of missing values even under extreme missingness. We benchmark aps-lm in a simulation study. aps-lm showed greater prediction accuracy and reduced bias compared to popular imputation strategies under a wide range of scenarios including variation of sample size, goodness of fit, missing value type, and covariance structure. Finally, as a proof-of-principle, we apply aps-lm in the context of epigenetic aging clocks, linear models that predict a person's biological age from epigenetic data with promising clinical applications.

Improvement in Epigenetic Aging Clock Induced by BioBran Containing Rice Kefiran in Relation to Various Biomarkers: A Pilot Study.

Many lifestyle-related diseases such as cancer, dementia, myocardial infarction, and stroke are known to be caused by aging, and the WHO's ICD-11 (International Classification of Diseases, 11th edition) created the code "aging-related" in 2022. In other words, aging is irreversible but aging-related diseases are reversible, so taking measures to treat them is important for health longevity and preventing other diseases. Therefore, in this study, we used BioBran containing rice kefiran as an approach to improve aging. Rice kefiran has been reported to improve the intestinal microflora, regulate the intestines, and have anti-aging effects. BioBran has also been reported to have antioxidant effects and improve liver function, and human studies have shown that it affects the diversity of the intestinal microbiota. Quantitative measures of aging that correlate with disease risk are now available through the epigenetic clock test, which examines the entire gene sequence and determines biological age based on the methylation level. Horvath's Clock is the best known of many epigenetic clock tests and was published by Steve Horvath in 2013. In this study, we examine the effect of using Horvath's Clock to improve aging and report on the results, which show a certain effect.

Neighborhood Disadvantage and Parenting in Early Adolescence Predict Epigenetic Aging and Mortality Risk in Adulthood.

Youth who grow up in disadvantaged neighborhoods experience poorer health later in life, but little is known about the biological mechanisms underlying these effects and socioenvironmental factors that may protect youth from the biological embedding of neighborhood adversity. This study tests whether supportive and consistent parenting buffers associations between neighborhood disadvantage in early adolescence and epigenetic aging in adulthood. A community sample from Birmingham, Alabama, USA (N = 343; 57% female; 81% Black, 19% White) was assessed in early adolescence (T1; ages 11 and 13) and adulthood (T2; age 27). At T1, neighborhood poverty was derived from census data and neighborhood disorder was reported by caregivers. Both youth and parents reported on parental discipline and nurturance. At T2, methylation of salivary DNA was used to derive a mortality risk index and Hannum, Horvath, PhenoAge, and GrimAge epigenetic age estimators. Regression analyses revealed that neighborhood disadvantage was associated with accelerated epigenetic aging and/or mortality risk only when combined with high levels of harsh and inconsistent discipline and low child-reported parental nurturance. These findings identify epigenetic aging and mortality risk as relevant mechanisms through which neighborhood adversity experienced in adolescence may affect later health; they also point to the importance of supportive and consistent parenting for reducing the biological embedding of neighborhood adversity in early adolescence.

The pace of biological aging helps explain the association between insomnia and chronic low back pain.

Chronic low back pain (cLBP) is associated with insomnia and advanced age. Emerging evidence suggests that the severity of both sleep disorders (like insomnia) and chronic pain are associated with a faster pace of biological aging. We aimed to determine whether the pace of biological age mediates the relationship between insomnia and the impact of cLBP in a sample of community-dwelling adults ages 19 to 85 years. Participants (49 with no pain, 32 with low-impact pain, and 37 with high-impact pain) completed sociodemographic, pain, insomnia, and short physical performance battery assessments. We calculated the pace of biological aging using DunedinPACE from blood leukocyte DNA. On average, individuals with high-impact cLBP had significantly faster biological aging than those with low-impact and no chronic pain (p < .001). Bivariate associations of DunedinPACE scores with insomnia severity and functional performance were significant at p < .01 (rs = 0.324 and -0.502, respectively). After adjusting for race and sex, the association of insomnia severity and the impact of cLBP was partially mediated by the pace of biological aging (ß = 0.070, p < .001). Also, the association of insomnia severity with functional performance was partially mediated by the pace of biological aging (ß = -0.105, p < .001). Thus, insomnia remains strongly predictive of cLBP outcomes, and the pace of biological aging helps explain this association. Future prospective studies with repeated assessments are needed to uncover the directionality of these complex relationships and ultimately develop interventions to manage cLBP.

Is CpG Density the Link between Epigenetic Aging and Lifespan?

The genetic mechanisms contributing to lifespan variation remain unresolved. Based on recent conceptual advances in our understanding of epigenetic potential and the relocalization of chromatin modifiers (RCM), we hypothesize that increased CpG density is protective against age-related erosion of the epigenetic landscape and may explain interspecific variation in lifespan.

Long-term variability in physiological measures in relation to mortality and epigenetic aging: prospective studies in the USA and China.

BACKGROUND: Visit-to-visit body weight variability (BWV), pulse rate variability (PRV), and blood pressure variability (BPV) have been respectively linked to multiple health outcomes. The associations of the combination of long-term variability in physiological measures with mortality and epigenetic age acceleration (EAA) remain largely unknown. METHODS: We constructed a composite score of physiological variability (0-3) of large variability in BWV, PRV, and BPV (the top tertiles) in 2006/2008-2014/2016 in the Health and Retirement Study (HRS) and 2011-2015 in the China Health and Retirement Longitudinal Study (CHARLS). All-cause mortality was documented through 2018. EAA was calculated using thirteen DNA methylation-based epigenetic clocks among 1047 participants in a substudy of the HRS. We assessed the relation of the composite score to the risk of mortality among 6566 participants in the HRS and 6906 participants in the CHARLS by Cox proportional models and then investigated its association with EAA using linear regression models. RESULTS: A higher score of variability was associated with higher mortality risk in both cohorts (pooled hazard ratio [HR] per one-point increment, 1.27; 95% confidence interval [CI], 1.18, 1.39; P-heterogeneity = 0.344), after adjustment for multiple confounders and baseline physiological measures. Specifically, each SD increment in BWV, PRV, and BPV was related to 21% (95% CI: 15%, 28%), 6% (0%, 13%), and 12% (4%, 19%) higher hazard of mortality, respectively. The composite score was significantly related to EAA in second-generation clocks trained on health outcomes (e.g., standardized coefficient = 0.126 in the Levine clock, 95% CI: 0.055, 0.196) but not in most first-generation clocks trained on chronological age. CONCLUSIONS: Larger variability in physiological measures was associated with a higher risk of mortality and faster EAA.

Associations between prenatal phthalate exposure and childhood epigenetic age acceleration.

BACKGROUND: Phthalates, a group of pervasive endocrine-disrupting chemicals found in plastics and personal care products, have been associated with a wide range of developmental and health outcomes. However, their impact on biomarkers of aging has not been characterized. We tested associations between prenatal exposure to 11 phthalate metabolites on epigenetic aging in children at birth, 7, 9, and 14 years of age. We hypothesized that prenatal phthalate exposure will be associated with epigenetic age acceleration measures at birth and in early childhood, with patterns dependent on sex and timing of DNAm measurement. METHODS: Among 385 mother-child pairs from the CHAMACOS cohort, we measured DNAm at birth, 7, 9, and 14 years of age, and utilized adjusted linear regression to assess the association between prenatal phthalate exposure and Bohlin's Gestational Age Acceleration (GAA) at birth and Intrinsic Epigenetic Age Acceleration (IEAA) throughout childhood. Additionally, quantile g-computation was utilized to assess the effect of the phthalate mixture on GAA at birth and IEAA throughout childhood. RESULTS: We found a negative association between prenatal di (2-ethylhexyl) phthalate (DEHP) exposure and IEAA among males at age 7 (-0.62 years; 95% CI:-1.06 to -0.18), and a marginal negative association between the whole phthalate mixture and GAA among males at birth (-1.54 days, 95% CI: -2.79 to -0.28), while most other associations were nonsignificant. CONCLUSIONS: Our results suggest that prenatal exposure to certain phthalates is associated with epigenetic aging in children. Additionally, our findings suggest that the influence of prenatal exposures on epigenetic age may only manifest during specific periods of child development, and studies relying on DNAm measurements solely from cord blood or single time points may overlook potential relationships.

Prenatal exposures to per- and polyfluoroalkyl substances and epigenetic aging in umbilical cord blood: The Healthy Start study.

BACKGROUND: Per- and polyfluoroalkyl substances (PFAS) are ubiquitous, environmentally persistent chemicals, and prenatal exposures have been associated with adverse child health outcomes. Prenatal PFAS exposure may lead to epigenetic age acceleration (EAA), defined as the discrepancy between an individual's chronologic and epigenetic or biological age. OBJECTIVES: We estimated associations of maternal serum PFAS concentrations with EAA in umbilical cord blood DNA methylation using linear regression, and a multivariable exposure-response function of the PFAS mixture using Bayesian kernel machine regression. METHODS: Five PFAS were quantified in maternal serum (median: 27 weeks of gestation) among 577 mother-infant dyads from a prospective cohort. Cord blood DNA methylation data were assessed with the Illumina HumanMethylation450 array. EAA was calculated as the residuals from regressing gestational age on epigenetic age, calculated using a cord-blood specific epigenetic clock. Linear regression tested for associations between each maternal PFAS concentration with EAA. Bayesian kernel machine regression with hierarchical selection estimated an exposure-response function for the PFAS mixture. RESULTS: In single pollutant models we observed an inverse relationship between perfluorodecanoate (PFDA) and EAA (-0.148 weeks per log-unit increase, 95% CI: -0.283, -0.013). Mixture analysis with hierarchical selection between perfluoroalkyl carboxylates and sulfonates indicated the carboxylates had the highest group posterior inclusion probability (PIP), or relative importance. Within this group, PFDA had the highest conditional PIP. Univariate predictor-response functions indicated PFDA and perfluorononanoate were inversely associated with EAA, while perfluorohexane sulfonate had a positive association with EAA. CONCLUSIONS: Maternal mid-pregnancy serum concentrations of PFDA were negatively associated with EAA in cord blood, suggesting a pathway by which prenatal PFAS exposures may affect infant development. No significant associations were observed with other PFAS. Mixture models suggested opposite directions of association between perfluoroalkyl sulfonates and carboxylates. Future studies are needed to determine the importance of neonatal EAA for later child health outcomes.

Infant epigenetic aging moderates the link between Black maternal childhood trauma and offspring symptoms of psychopathology.

Although offspring of women exposed to childhood trauma exhibit elevated rates of psychopathology, many children demonstrate resilience to these intergenerational impacts. Among the variety of factors that likely contribute to resilience, epigenetic processes have been suggested to play an important role. The current study used a prospective design to test the novel hypothesis that offspring epigenetic aging - a measure of methylation differences that are associated with infant health outcomes - moderates the relationship between maternal exposure to childhood adversity and offspring symptomatology. Maternal childhood adversity was self-reported during pregnancy via the ACEs survey and the CTQ, which assessed total childhood trauma as well as maltreatment subtypes (i.e., emotional, physical, and sexual abuse). Offspring blood samples were collected at or shortly after birth and assayed on a DNA methylation microarray, and offspring symptomatology was assessed with the CBCL/1.5-5 when offspring were 2-4 years old. Results indicated that maternal childhood trauma, particularly sexual abuse, was predictive of offspring symptoms (ps = 0.003-0.03). However, the associations between maternal sexual abuse and offspring symptomatology were significantly attenuated in offspring with accelerated epigenetic aging. These findings further our understanding of how epigenetic processes may contribute to and attenuate the intergenerational link between stress and psychopathology.

Adolescent peer struggles predict accelerated epigenetic aging in midlife.

This study examined struggles to establish autonomy and relatedness with peers in adolescence and early adulthood as predictors of advanced epigenetic aging assessed at age 30. Participants (N = 154; 67 male and 87 female) were observed repeatedly, along with close friends and romantic partners, from ages 13 through 29. Observed difficulty establishing close friendships characterized by mutual autonomy and relatedness from ages 13 to 18, an interview-assessed attachment state of mind lacking autonomy and valuing of attachment at 24, and self-reported difficulties in social integration across adolescence and adulthood were all linked to greater epigenetic age at 30, after accounting for chronological age, gender, race, and income. Analyses assessing the unique and combined effects of these factors, along with lifetime history of cigarette smoking, indicated that each of these factors, except for adult social integration, contributed uniquely to explaining epigenetic age acceleration. Results are interpreted as evidence that the adolescent preoccupation with peer relationships may be highly functional given the relevance of such relationships to long-term physical outcomes.

Methylation-based markers of aging and lifestyle-related factors and risk of breast cancer: a pooled analysis of four prospective studies.

BACKGROUND: DNA methylation in blood may reflect adverse exposures accumulated over the lifetime and could therefore provide potential improvements in the prediction of cancer risk. A substantial body of research has shown associations between epigenetic aging and risk of disease, including cancer. Here we aimed to study epigenetic measures of aging and lifestyle-related factors in association with risk of breast cancer. METHODS: Using data from four prospective case-control studies nested in three cohorts of European ancestry participants, including a total of 1,655 breast cancer cases, we calculated three methylation-based measures of lifestyle factors (body mass index [BMI], tobacco smoking and alcohol consumption) and seven measures of epigenetic aging (Horvath-based, Hannum-based, PhenoAge and GrimAge). All measures were regression-adjusted for their respective risk factors and expressed per standard deviation (SD). Odds ratios (OR) and 95% confidence intervals (CI) were calculated using conditional or unconditional logistic regression and pooled using fixed-effects meta-analysis. Subgroup analyses were conducted by age at blood draw, time from blood sample to diagnosis, oestrogen receptor-positivity status and tumour stage. RESULTS: None of the measures of epigenetic aging were associated with risk of breast cancer in the pooled analysis: Horvath 'age acceleration' (AA): OR per SD = 1.02, 95%CI: 0.95-1.10; AA-Hannum: OR = 1.03, 95%CI:0.95-1.12; PhenoAge: OR = 1.01, 95%CI: 0.94-1.09 and GrimAge: OR = 1.03, 95%CI: 0.94-1.12, in models adjusting for white blood cell proportions, body mass index, smoking and alcohol consumption. The BMI-adjusted predictor of BMI was associated with breast cancer risk, OR per SD = 1.09, 95%CI: 1.01-1.17. The results for the alcohol and smoking methylation-based predictors were consistent with a null association. Risk did not appear to substantially vary by age at blood draw, time to diagnosis or tumour characteristics. CONCLUSION: We found no evidence that methylation-based measures of aging, smoking or alcohol consumption were associated with risk of breast cancer. A methylation-based marker of BMI was associated with risk and may provide insights into the underlying associations between BMI and breast cancer.

Epigenetic age predictors in community-dwelling adults with high impact knee pain.

Gerontological research reveals considerable interindividual variability in aging phenotypes, and emerging evidence suggests that high impact chronic pain may be associated with various accelerated biological aging processes. In particular, epigenetic aging is a robust predictor of health-span and disability compared to chronological age alone. The current study aimed to determine whether several epigenetic aging biomarkers were associated with high impact chronic pain in middle to older age adults (44-78 years old). Participants (n = 213) underwent a blood draw, demographic, psychosocial, pain and functional assessments. We estimated five epigenetic clocks and calculated the difference between epigenetic age and chronological age, which has been previously reported to predict overall mortality risk, as well as included additional derived variables of epigenetic age previously associated with pain. There were significant differences across Pain Impact groups in three out of the five epigenetic clocks examined (DNAmAge, DNAmPhenoAge and DNAmGrimAge), indicating that pain-related disability during the past 6 months was associated with markers of epigenetic aging. Only DNAmPhenoAge and DNAmGrimAge were associated with higher knee pain intensity during the past 48 h. Finally, pain catastrophizing, depressive symptomatology and more neuropathic pain symptoms were significantly associated with an older epigenome in only one of the five epigenetic clocks (i.e. DNAmGrimAge) after correcting for multiple comparisons (corrected p's < 0.05). Given the scant literature in relation to epigenetic aging and the complex experience of pain, additional research is needed to understand whether epigenetic aging may help identify people with chronic pain at greater risk of functional decline and poorer health outcomes.

Associations between epigenetic age acceleration and infertility.

STUDY QUESTION: Is the use of ART, a proxy for infertility, associated with epigenetic age acceleration? SUMMARY ANSWER: The epigenetic age acceleration measured by Dunedin Pace of Aging methylation (DunedinPoAm) differed significantly between non-ART and ART mothers. WHAT IS KNOWN ALREADY: Among mothers who used ART, epigenetic age acceleration may be associated with low oocyte yield and poor ovarian response. However, the difference in epigenetic age acceleration between non-ART and ART mothers (or even fathers) has not been examined. STUDY DESIGN, SIZE, DURATION: The Norwegian Mother, Father and Child Cohort Study (MoBa) recruited pregnant women and their partners across Norway at around 18 gestational weeks between 1999 and 2008. Approximately 95 000 mothers, 75 000 fathers and 114 000 children were included. Peripheral blood samples were taken from mothers and fathers at ultrasound appointments or from mothers at childbirth, and umbilical cord blood samples were collected from the newborns at birth. PARTICIPANTS/MATERIALS, SETTING, METHODS: Among the MoBa participants, we selected 1000 couples who conceived by coitus and 894 couples who conceived by IVF (n = 525) or ICSI (n = 369). We measured their DNA methylation (DNAm) levels using the Illumina MethylationEPIC array and calculated epigenetic age acceleration. A linear mixed model was used to examine the differences in five different epigenetic age accelerations between non-ART and ART parents. MAIN RESULTS AND THE ROLE OF CHANCE: We found a significant difference in the epigenetic age acceleration calculated by DunedinPoAm between IVF and non-ART mothers (0.021 years, P-value = 2.89E-06) after adjustment for potential confounders. Further, we detected elevated DunedinPoAm in mothers with tubal factor infertility (0.030 years, P-value = 1.34E-05), ovulation factor (0.023 years, P-value = 0.0018) and unexplained infertility (0.023 years, P-value = 1.39E-04) compared with non-ART mothers. No differences in epigenetic age accelerations between non-ART and ICSI fathers were found. DunedinPoAm also showed stronger associations with smoking, education and parity than the other four epigenetic age accelerations. LIMITATIONS, REASONS FOR CAUTION: We were not able to determine the directionality of the causal pathway between the epigenetic age accelerations and infertility. Since parents' peripheral blood samples were collected after conception, we cannot rule out the possibility that the epigenetic profile of ART mothers was influenced by the ART treatment. Hence, the results should be interpreted with caution, and our results might not be generalizable to non-pregnant women. WIDER IMPLICATIONS OF THE FINDINGS: A plausible biological mechanism behind the reported association is that IVF mothers could be closer to menopause than non-ART mothers. The pace of decline of the ovarian reserve that eventually leads to menopause varies between females yet, in general, accelerates after the age of 30, and some studies show an increased risk of infertility in females with low ovarian reserve. STUDY FUNDING/COMPETING INTEREST(S): This study was partly funded by the Research Council of Norway (Women's fertility, project no. 320656) and through its Centres of Excellence Funding Scheme (project no. 262700). M.C.M. has received funding from the European Research Council (ERC) under the European Union's Horizon 2020 research and innovation programme (grant agreement number 947684). The authors declare no conflict of interest. TRIAL REGISTRATION NUMBER: N/A.

Mortality and morbidity in ageing men: Biology, Lifestyle and Environment.

Males live shorter lives than women in all countries. The universality of shorter male life expectancy is a 21st Century phenomena. It occurs with the decline in infectious diseases and the rise in cardiovascular diseases accounting for mortality. Male/female differences in morbidity are not as succinctly characterized. Men have a higher prevalence of lethal diseases, which is linked to their lower life expectancy. Women have more non-lethal conditions such as depression and arthritis; which may also be linked in part to longer survival. Men have better physical functioning and less disability which is partly explained by gender differences in diseases and also by their greater strength, size, and stamina. Gender differences in risk factors for disease have changed over time with the prevalence and treatment of risk as well as differential behavior by gender. Examination of what are seen as basic molecular and cellular measures related to aging indicates men age faster than women; however, even these basic biological measures result from a combination of biology, behavior, and social factors.

Association between depression and epigenetic age acceleration: A co-twin control study.

INTRODUCTION: Prior studies have shown inconsistent findings of an association between depression and epigenetic aging. DNA methylation (DNAm) age acceleration can measure biological aging. We adopted a robust co-twin control study design to examine whether depression is associated with DNAm age acceleration after accounting for the potential confounding influences of genetics and family environment. METHODS: We analyzed data on a sub-cohort of the Vietnam Era Twin Registry. A total of 291 twins participated at baseline and 177 at follow-up visit after a mean of 11.7 years, with 111 participants having DNA samples for both time points. Depression was measured using the Beck Depression Inventory II (BDI-II). Six measures of DNAm age acceleration were computed at each time point, including Horvath's DNAm age acceleration (HorvathAA), intrinsic epigenetic age acceleration (IEAA), Hannum's DNAm age acceleration (HannumAA), extrinsic epigenetic age acceleration (EEAA), GrimAge acceleration (GrimAA), and PhenoAge acceleration (PhenoAA). Mixed-effects modeling was used to assess the within-pair association between depression and DNAm age acceleration. RESULTS: At baseline, a 10-unit higher BDI-II total score was associated with HannumAA (0.73 years, 95% confidence interval [CI] 0.13-1.33, p = .019) and EEAA (0.94 years, 95% CI 0.22-1.66, p = .012). At follow-up, 10-unit higher BDI-II score was associated with PhenoAA (1.32 years, 95% CI 0.18-2.47, p = .027). CONCLUSION: We identified that depression is associated with higher levels of DNAm age acceleration. Further investigation is warranted to better understand the underlying mechanisms for the potential causal relationship between depression and accelerated aging.