Biological Age Acceleration Research Articles

Epigenetic clock analysis in methamphetamine dependence

Methamphetamine (MA) is used worldwide and causes serious public health and social problems. MA affects the central nervous, cardiac, and immune systems, which causes neuropsychiatric and cardiovascular diseases and infection. Epigenetic changes, including DNA methylation (DNAm), are associated with various clinical phenotypes of MA abuse. DNAm is related to biological aging and health risks; hence, we aimed to assess the changes in biological aging in MA dependence using the DNAm age and DNA methylation-based telomere length (DNAmTL). We used five measures of DNAm age (HorvathAge, HannumAge, SkinBloodAge, PhenoAge, and GrimAge), DNAmTL, and DNAm-based age-predictive factors (plasma proteins and blood cell composition). We compared patients with MA dependence and healthy controls (n = 24 each) using the DNAm profiles obtained from whole-blood samples. Patients with MA dependence showed significant acceleration in PhenoAge and GrimAge, as well as a trend for significant acceleration in DNAmTL. Following adjustment for confounding factors, MA dependence was significantly associated with accelerations in PhenoAge, GrimAge, and DNAmTL, as well as alterations in DNAm-based age-predictive factors (beta-2-microglobulin, granulocytes, and naive cluster of differentiation 4+ T cells). Our results suggested an acceleration of biological aging and specific changes in the DNAm of age- predictive factors in MA dependence.

Effect of metformin on the epigenetic age of peripheral blood in patients with diabetes mellitus.

Background: Metformin has been proven to have an antiaging effect. However, studies on how metformin affects global epigenetic regulation and its effect on the epigenetic clock in diabetes mellitus (DM) patients are limited. This study aims to investigate the impact of metformin on the epigenetic age in subjects with type 2 DM. Results: We collected the peripheral blood of the metformin group and the no-metformin group of the 32 DM patients. Three previously established epigenetic clocks (Hannum, Horvath, and DNAmPhenoAge) were used to estimate the epigenetic age acceleration of the two groups. We defined biological age acceleration for each group by comparing the estimated biological age with the chronological age. Results were presented as follows: 1) all three epigenetic clocks were strongly correlated with chronological age. 2) We found a strong association between metformin intake and slower epigenetic aging by Horvath’s clock and Hannum’s clock. Conclusions: Here, we found an association between metformin intake and slower epigenetic aging.

Reverse inflammaging: Long-term effects of HCV cure on biological age

Chronic hepatitis C virus (HCV) infection can be cured with direct-acting antivirals (DAAs). However, not all sequelae of chronic hepatitis C appear to be completely reversible after sustained virologic response (SVR). Recently, chronic viral infections have been shown to be associated with biological age acceleration defined by the epigenetic clock. The aim of this study was to investigate whether chronic HCV infection is associated with epigenetic changes and biological age acceleration and whether this is reversible after SVR. We included 54 well-characterized individuals with chronic hepatitis C who achieved SVR after DAA therapy at three time points: DAA treatment initiation, end of treatment, and long-term follow-up (median 96 weeks after end of treatment). Genome-wide DNA methylation status was determined in peripheral blood mononuclear cells (PBMCs) and used to calculate epigenetic age acceleration (EAA) using Horvath's clock. Individuals with HCV had an overall significant EAA of 3.12 years at baseline compared with -2.61 years in the age- and sex-matched reference group (p <0.00003). HCV elimination resulted in a significant long-term increase in DNA methylation dominated by hypermethylated CpGs in all patient groups. Accordingly, EAA decreased to 1.37 years at long-term follow-up. The decrease in EAA was significant only between the end of treatment and follow-up (p= 0.01). Interestingly, eight individuals who developed hepatocellular carcinoma after SVR had the highest EAA and showed no evidence of reversal after SVR. Our data contribute to the understanding of the biological impact of HCV elimination after DAA therapy and demonstrate that HCV elimination can lead to "reverse inflammaging". In addition, our data support the potential use of biological age as a biomarker for HCV sequelae after SVR. Chronic hepatitis C virus infection is now curable with direct-acting antivirals, but it remains unclear whether hepatitis C sequelae are fully reversible after viral elimination. Our results suggest that epigenetic changes or acceleration of biological age are reversible in principle, but this requires time, while a lack of reversibility appears to be associated with the development of hepatocellular carcinoma. While most clinical risk scores now take chronological age into account, it may be worthwhile to explore how biological age might improve these scores in the future. Biological age may be a cornerstone for the individualized clinical assessment of patients in the future, as it better reflects patients' lifestyle and environmental exposures over decades.

Role of sleep quality in the acceleration of biological aging and its potential for preventive interaction on air pollution insults: findings from the UK Biobank cohort

Role of sleep quality in the acceleration of biological aging and its potential for preventive interaction on air pollution insults: findings from the UK Biobank cohort

Lifetime discrimination in low to middle income mothers and cellular aging: A prospective analysis

BackgroundExperiences of discrimination on the basis of race, ethnicity, and other characteristics are associated with adverse health outcomes, including elevated rates of morbidity in later life and earlier mortality. Acceleration of biological aging is a plausible pathway linking discrimination to disease risk. The objective of this study was to examine the relationship of self-reported lifetime and everyday discrimination to women's telomere length several years after birth of a child in a longitudinal cohort study. MethodsThe Community Child Health Network (CCHN) conducted a community-based participatory research project focused on racial, ethnic, and socioeconomic disparities in maternal and child health. Data for the current substudy are from a longitudinal cohort study in 3 of the 5 project sites. This multi-site community-based longitudinal study was conducted in Lake County, IL north of Chicago, Washington, D.C., and rural North Carolina. Participants were low to middle-income mothers (N = 103) with a primary identity of Hispanic/Latina, Black, or non-Hispanic White who rated their experience of everyday and lifetime discrimination during an at-home interview one-month postpartum. Buccal samples were collected to assay buccal cell telomere length several years later when a consecutive child was 3–5 years of age. Telomere length derived from buccal cells was used as a biomarker indicating cellular aging and a risk factor for age-related disease. ResultsMothers (18–39 years old) who reported higher lifetime discrimination had shorter telomere length an average of 5.6 years later (B = −0.22 [SE = 0.04], p < 0.001). Mother's reports of everyday discrimination were not significantly related to telomere length (0.01[0.01], p = 0.15). ConclusionsThese findings suggest that lifetime exposure to discrimination, but not necessarily current reports of everyday discrimination, may increase biological aging as indicated by shorter buccal cell telomere length, providing evidence of a plausible route through which discrimination contributes to increased risk for earlier onset aging and age-related disease in women.

Urinary phthalate metabolites and their mixtures are associated with advanced sperm epigenetic aging in a general population

IntroductionWe have recently shown that sperm epigenetic age (SEA), a surrogate measure of biological aging in sperm, is associated with couples’ time-to-pregnancy (TTP). Advanced SEA was also observed among smokers, suggesting its susceptibility to environmental exposures. Therefore, we assessed the association between urinary phthalate metabolites and SEA in male partners of couples planning to conceive among the general population. MethodThe Longitudinal Investigation of Fertility and the Environment (LIFE) Study was a prospective multi-site and general population cohort study of couples who were interested in becoming pregnant. Among male partners (n = 333), eleven urinary phthalate metabolites were measured and SEA was previously developed using Super Learner ensemble algorithm. Multivariable linear regression was used to evaluate associations of SEA with individual metabolites. Bayesian kernel machine regression (BKMR), quantile g-computation (qgcomp) and weighted quantile sum (WQS) models were used for mixture analyses. Covariates included were BMI, cotinine, race and urinary creatinine. ResultIn the single metabolite multivariate analyses, nine (82%) phthalate metabolites displayed positive trends with SEA (range: 0.05–0.47 years). Of these metabolites, advanced SEA was significantly associated with interquartile range increases in exposure of three phthalates [MEHHP (β = 0.23, 95% CI: 0.03, 0.43, p = 0.03), MMP (β = 0.24, 95% CI: 0.01, 0.47, p = 0.04), and MiBP (β = 0.47, 95% CI: 0.14, 0.81, p = 0.01)]. Additionally, in BKMR and qgcomp (p = 0.06), but not WQS models, phthalate mixtures showed an overall positive trend with SEA, with MiBP, MMP and MBzP as major drivers of the mixture effects. ConclusionThis is the first study that combined single exposure and mixture models to associate male phthalate exposures with advanced epigenetic aging of sperm in men planning to conceive among the general population. Our findings suggest that phthalate exposure may contribute to the acceleration of biological aging of sperm.

Biological ageing and the risks of all-cause and cause-specific mortality among people with diabetes: a prospective cohort study

BackgroundThe aetiology of diabetes is complex with limited treatment strategies. Growing animal studies have shown that targeted antiageing can improve the outcomes of diabetes. However, population evidence is limited. This...

DNA Methylation "GrimAge" Acceleration Mediates Sex/Gender Differences in Verbal Memory and Processing Speed: Findings From the Health and Retirement Study.

Whether sex/gender differences in rates of biological aging mediate sex/gender differences in cognition in older adults has not been fully examined. The aim of the current study was to investigate this association. Data from up to 1 928 participants (mean age = 75, standard deviation = 7.04, female = 57%) who took part in the 2016 Harmonized Cognitive Assessment Protocol and Venous Blood Study; substudies of the Health and Retirement Study were included in the current study. The residuals from 4 age-adjusted epigenetic clocks (Horvath, Hannum, PhenoAge, and GrimAge) were used to measure biological age acceleration. Sex/gender differences in cognition were tested using a series of analyses of covariance. Mediation analyses tested whether the measures of age acceleration accounted for these sex/gender differences, controlling for age, education, smoking status, and white blood cell count. Women outperformed men on measures of verbal learning, verbal memory, visual scanning, and processing speed. No other significant sex/gender differences were identified. Results from mediation analyses revealed that women's slower rates of GrimAge fully accounted for their faster processing speeds and partially accounted for their better performances on verbal learning, verbal memory, and visual scanning measures. None of the other measures of age acceleration were significant mediators. Accounting for sex/gender differences in biological aging may differentiate between cognitive sex/gender differences that are driven by universal (ie, age-related) versus sex-specific mechanisms. More broadly, these findings support the growing evidence that the GrimAge clock outperforms other clocks in predicting cognitive outcomes.

P88. Psychological Resilience Protects Against Stress Effects on Insulin Resistance and Epigenetic Aging

Our society is experiencing more stress than ever before, and chronic stress has been linked to negative long-term health outcomes. This raises the possibility these consequences of stress might be the result of accelerated biological aging. While psychological resilience protects against the mental consequences, of stress it is unclear if it also protects against the physical effects as well. In this study, we examined whether psychological resilience affects stress-associated biological age acceleration.

P095 Epigenetic clocks have the potential to predict future grip strength in males but not females

Abstract Background/Aims Sarcopenia and muscle ageing are associated with substantial morbidity and mortality for the individual and significant costs to healthcare budgets. However, if we can identify those at particular risk of muscle decline it may be possible to intervene, prevent further deterioration and improve the musculoskeletal health of the ageing population. DNA methylation accumulates across the lifecourse and provides the basis for biological clocks, generating a measure of age acceleration (i.e. that an individual is biologically older or younger than their chronological age would suggest). An example is the GrimAge clock which was designed to estimate remaining longevity and thus may potentially represent a novel risk marker for muscle deterioration. We aimed to investigate whether there is an association between methylation-measured age acceleration and future grip strength in a group of community-dwelling older adults. Methods This study is based within the Hertfordshire Cohort Study. At baseline, participants attended research visits where health-related questionnaires were completed and blood samples were collected. DNA was extracted from peripheral blood leukocytes and DNA methylation at CpG sites was measured using the Infinium Human Methylation Beadchip arrays (Illumina Inc., San Diego, CA) (450k, n = 99 and 850k, n = 326). After pre-processing, GrimAge epigenetic age acceleration was measured, using the array-specific publicly available algorithms, and standardised to an SD scale. Grip strength was ascertained using the JAMAR dynamometer at baseline and follow-up. Linear regression was used to examine GrimAge acceleration in relation to grip strength at baseline and follow-up in unadjusted models and those adjusted for age, height and BMI. Results A total of 425 participants (213 males and 212 females) were included in our analyses. The mean age at baseline was 64.1 years (SD 2.6) for males and 65.9 years (SD 2.7) for females. The median follow-up time was 11.6 years (IQR 11.0-12.4) and mean GrimAge at baseline was 58.4 years (SD 5.6). Higher GrimAge acceleration was significantly associated with lower grip strength at baseline (β= -1.43kg [95% CI: -2.39,-0.47] per SD greater age acceleration in univariate model, p &amp;lt; 0.01) in unadjusted and adjusted models and at follow-up (β= -1.25kg [-2.24,-0.26] per SD, p &amp;lt; 0.02). No significant associations were observed in females. Conclusion Our results suggest that greater GrimAge acceleration, as a measure of biological age acceleration, is significantly associated with lower grip strength after approximately a decade of follow-up. However, this association was only observed in males and not in females. The GrimAge clock was designed using methylation surrogates of age-related plasma proteins and smoking pack years, and it may be that the variation in these was more marked in our male population compared to females. Further work is required to investigate and replicate the above association. Disclosure N.R. Fuggle: None. L. Westbury: None. F. Reswan: None. N. Graham: None. N. Kitaba: None. K.A. Ward: None. K.A. Ward: None. N. Harvey: None. J. Holloway: None. E. Dennison: None. C. Cooper: None.

Role of sleep quality in the acceleration of biological aging and its potential for preventive interaction on air pollution insults: Findings from the UK Biobank cohort.

Sleep has been associated with aging and relevant health outcomes, but the causal relationship remains inconclusive. In this study, we investigated the associations of sleep behaviors with biological ages (BAs) among 363,886 middle and elderly adults from UK Biobank. Sleep index (0 [worst]–6 [best]) of each participant was retrieved from the following six sleep behaviors: snoring, chronotype, daytime sleepiness, sleep duration, insomnia, and difficulties in getting up. Two BAs, the KDM‐biological age and PhenoAge, were estimated by corresponding algorithms based on clinical traits, and their residual discrepancies with chronological age were defined as the age accelerations (AAs). We first observed negative associations between the sleep index and the two AAs, and demonstrated that the change of AAs could be the consequence of sleep quality using Mendelian randomization with genetic risk scores of sleep index and BAs. Particularly, a one‐unit increase in sleep index was associated with 0.104‐ and 0.119‐year decreases in KDM‐biological AA and PhenoAge acceleration, respectively. Air pollution is another key driver of aging. We further observed significant independent and joint effects of sleep and air pollution (PM2.5 and NO2) on AAs. Sleep quality also showed a modifying effect on the associations of elevated PM2.5 and NO2 levels with accelerated AAs. For instance, an interquartile range increase in PM2.5 level was associated with 0.009‐, 0.044‐, and 0.074‐year increase in PhenoAge acceleration among people with high (5–6), medium (3–4), and low (0–2) sleep index, respectively. Our findings elucidate that better sleep quality could lessen accelerated biological aging resulting from air pollution.

Childhood police encounters, social isolation and epigenetic age acceleration among older U.S. adults

ObjectivesThis study examined associations of childhood police encounters with biological age acceleration in later life, and their mediation by subjective or objective social isolation. MethodsData were from the Health and Retirement Study, nationally representative of older U.S. adults. Age acceleration was proxied through newly available epigenetic measures. Doubly robust estimation was used to establish baseline linkages, and heterogenous treatment effect models to examine variations in effects by one's increasing propensity for early police encounters. Mediation analysis was through a recently developed regression-with-residuals approach for structural nested mean models. ResultsChildhood police encounters was prospectively associated with age acceleration. Those with such early experiences also reported more loneliness and isolation from their community, although their ties to family and friends seemed stronger. Associations did not significantly decline with increasing propensity for such childhood experiences. Treatment effects on age acceleration seemed partly mediated by loneliness and by community isolation. DiscussionFindings add to the growing evidence on the “long arm of childhood,” and highlight public health implications of policy-driven social exposures.

Biological Age Acceleration Is Lower in Women With Ischemic Stroke Compared to Men

Stroke onset in women occurs later in life compared with men. The underlying mechanisms of these differences have not been established. Epigenetic clocks, based on DNA methylation (DNAm) profiles, are the most accurate biological age estimate. Epigenetic age acceleration (EAA) measures indicate whether an individual is biologically younger or older than expected. Our aim was to analyze whether sexual dichotomy at age of stroke onset is conditioned by EAA. We used 2 DNAm datasets from whole blood samples of case-control genetic studies of ischemic stroke (IS), a discovery cohort of 374 IS patients (N women=163, N men=211), from GRECOS (Genotyping Recurrence Risk of Stroke) and SEDMAN (Dabigatran Study in the Early Phase of Stroke, New Neuroimaging Markers and Biomarkers) studies and a replication cohort of 981 IS patients (N women=411, N men=570) from BASICMAR register. We compared chronological age, 2 DNAm-based biomarkers of aging and intrinsic and extrinsic epigenetic age acceleration EAA (IEAA and extrinsic EAA, respectively), in IS as well as in individual IS etiologic subtypes. Horvath and Hannum epigenetic clocks were used to assess the aging rate. A proteomic study using the SOMAScan multiplex assay was performed on 26 samples analyzing 1305 proteins. Women present lower Hannum-extrinsic EAA values, whereas men have higher Hannum-extrinsic EAA values (women=-0.64, men=1.24, P=1.34×10-2); the same tendency was observed in the second cohort (women=-0.57, men=0.79, P=0.02). These differences seemed to be specific to cardioembolic and undetermined stroke subtypes. Additionally, 42 blood protein levels were associated with Hannum-extrinsic EAA (P<0.05), belonging to the immune effector process (P=1.54×10-6) and platelet degranulation (P<8.74×10-6) pathways. This study shows that sex-specific underlying biological mechanisms associated with stroke onset could be due to differences in biological age acceleration between men and women.

Accelerated epigenetic age and shortened telomere length based on DNA methylation in Nicolaides-Baraitser syndrome.

BackgroundNicolaides–Baraitser syndrome (NCBRS) is a rare disorder characterized by neurodevelopmental delays, seizures, and diverse physical characteristics. The DNA methylation (DNAm) profile in NCBRS is significantly different. DNAm is linked to the biological aging of cells and the health risks associated with biological aging. In this study, we examined changes in biological ages in NCBRS to provide insights into the prognosis and health risks of NCBRS.MethodsWe used a publicly available dataset to examine biological aging in NCBRS using DNAm‐based epigenetic ages, such as PhenoAge and GrimAge, as well as DNAm‐based estimator of telomere length (DNAmTL). We investigated 12 cases, clinically diagnosed as NCBRS, and 27 controls.ResultsCompared to controls, NCBRS cases exhibited significantly accelerated PhenoAge and GrimAge as well as significantly shortened DNAmTL.ConclusionThese results suggest an acceleration of biological aging in NCBRS and provide insights into the prognosis and health risks of NCBRS.

Integrative analysis of DNA methylation and gene expression identifies genes associated with biological aging in Alzheimer's disease.

IntroductionThe acceleration of biological aging is a risk factor for Alzheimer's disease (AD). Here, we performed weighted gene co‐expression network analysis (WGCNA) to identify modules and dysregulated genesinvolved in biological aging in AD.MethodsWe performed WGCNA to identify modules associated with biological clocks and hub genes of the module with the highest module significance. In addition, we performed differential expression analysis and association analysis with AD biomarkers.ResultsWGCNA identified five modules associated with biological clocks, with the module designated as “purple” showing the strongest association. Functional enrichment analysis revealed that the purple module was related to cell migration and death. Ten genes were identified as hub genes in purple modules, of which CX3CR1 was downregulated in AD and low levels of CX3CR1 expression were associated with AD biomarkers.ConclusionNetwork analysis identified genes associated with biological clocks, which suggests the genetic architecture underlying biological aging in AD.Highlights Examine links between Alzheimer's disease (AD) peripheral transcriptome and biological aging changes.Weighted gene co‐expression network analysis (WGCNA) found five modules related to biological aging.Among the hub genes of the module, CX3CR1 was downregulated in AD.The CX3CR1 expression level was associated with cognitive performance and brain atrophy.

Genetic and Phenotypic Evidence for the Causal Relationship Between Aging and COVID-19

Abstract Epidemiological studies revealed that the elderly and those with comorbidities are most susceptible to COVID-19. To understand how genetics affects the risk of COVID-19, we conducted a multi-instrument Mendelian Randomization (MR) analysis and found that the genetic variation that supports a longer life is significantly associated with the lower risk of COVID-19 infection, as well as being hospitalized after infected. The odds ratio is 0.31 (P = 9.7e-6) and 0.46 (P = 3.3e-4), respectively, per additional 10 years of life. We further applied aging clock models and detected an association between biological age acceleration and future incidence and severity of COVID-19 infection for all subjects and individuals free of chronic disease. Biological age acceleration was also significantly associated with the risk of death in COVID-19 patients. A bivariate genomic scan for age-related COVID-19 infection identified a key contribution of the Notch signaling pathway and immune system. Finally, we performed MR using 389 immune cell traits as exposure and observed a significant negative correlation between their effect on lifespan and COVID-19 risk, especially for B cell-related traits. More specifically, we discovered the lower CD19 level on B cells indicates an increased risk of COVID-19 and potentially decreases the lifespan expectancy, which is further validated in clinical data from COVID-19 patients. Our analysis suggests that the factors that accelerate aging and limit lifespan cause an increased COVID-19 risk. Thus, the interventions target these factors (e.g., reduce biological age), after further validation, may have the opportunity to reduce the risk of COVID-19.

Genetic and Phenotypic Evidence for the Causal Relationship Between Aging and COVID-19

Epidemiological studies revealed that the elderly and those with comorbidities are most susceptible to COVID-19. To understand how genetics affects the risk of COVID-19, we conducted a multi-instrument Mendelian Randomization (MR) analysis and found that the genetic variation that supports a longer life is significantly associated with the lower risk of COVID-19 infection, as well as being hospitalized after infected. The odds ratio is 0.31 (P = 9.7e-6) and 0.46 (P = 3.3e-4), respectively, per additional 10 years of life. We further applied aging clock models and detected an association between biological age acceleration and future incidence and severity of COVID-19 infection for all subjects and individuals free of chronic disease. Biological age acceleration was also significantly associated with the risk of death in COVID-19 patients. A bivariate genomic scan for age-related COVID-19 infection identified a key contribution of the Notch signaling pathway and immune system. Finally, we performed MR using 389 immune cell traits as exposure and observed a significant negative correlation between their effect on lifespan and COVID-19 risk, especially for B cell-related traits. More specifically, we discovered the lower CD19 level on B cells indicates an increased risk of COVID-19 and potentially decreases the lifespan expectancy, which is further validated in clinical data from COVID-19 patients. Our analysis suggests that the factors that accelerate aging and limit lifespan cause an increased COVID-19 risk. Thus, the interventions target these factors (e.g., reduce biological age), after further validation, may have the opportunity to reduce the risk of COVID-19.

Navigating Black Aging: The Biological Consequences of Stress and Depression.

Black persons in the United States are more likely to suffer from social inequality. Chronic stress caused by social inequality and racial discrimination results in weathering of the body that causes physiological dysregulation and biological age being higher than chronological age (accelerated aging). Depression has been linked to both racial discrimination and accelerated aging and accelerated aging has been demonstrated to be higher in Black than White persons, on average. However, we know little about accelerated aging across the life course in Black Americans. We used mixed-effects growth models to measure biological age acceleration, measured with cardiometabolic markers, over a 20-year period in Black participants of the Coronary Artery Risk Development in Young Adults Study who were aged 27-42 years at analytic baseline. We included an interaction between depressive symptoms and time to determine whether risk of depression was associated with a faster rate of biological aging. We found that the rate of biological aging increased over a 20-year span and that those at risk for depression had a faster rate of biological aging than those not at risk. We also found that various social factors were associated with biological age acceleration over time. Given the known association between perceived racial discrimination and depressive symptoms, we provide a novel instance of the long-term effects of social inequality. Specifically, biological age acceleration, a marker of physiological dysregulation, is associated with time among Black persons and more strongly associated among those with depressive symptoms.

Accelerated epigenetic aging in adults with Down Syndrome in the Argentine population

AbstractBackgroundLife expectancy of individuals with Down Syndrome (DS) is currently 60 years. From age 40 they have an increased risk of dementia and almost all of them have histopathological features of Alzheimer's disease (AD) in their brains. Also, it is known that the ε4 allele of the APOE gene and the R47H variant of TREM2 increase the risk of AD. DS is also associated with a group of clinical manifestations of accelerated aging. DNA methylation‐based biomarkers of ageing (epigenetic clocks) can be assessed by different models. It is known that DNA methylation age (DNAm) has a positive correlation with chronological age in disomic individuals while DS subjects exhibit an age acceleration effect in blood and brain.MethodWe determined the DNAm age of a cohort of seven participants with chromosome 21 trisomy (confirmed by G‐banding karyotyping). Median age was 49 years. Their cognitive status was assessed by clinical and neuropsychological evaluations. AD risk variants in APOE and TREM2 were analyzed by RFLP‐PCR. DNAm age was assessed in peripheral blood leukocytes, using the Illumina 850K platform. We used the Horvath’s epigenetic clock, based on the DNAm levels of 353 specific CpG sites.ResultFive participants exhibited the ε3/ε3 genotype in APOE and two of them the ε3/ε4 genotype. We did not observe the R47H risk variant in TREM2 in this group. Five participants showed a significant biological age acceleration and one participant’s DNAm age was similar to his chronological age. Of note, one participant showed a deceleration in the DNAm age. This participant also had multiple myeloma. It is known that the DNA methylation profile of multiple myeloma cells differs from normal plasma cells. On the other hand, we did not find a trend towards a greater presence of the risk allele ε4 or cognitive impairment in participants with a significant DNAm age acceleration.ConclusionThe majority participants presented an acceleration in their biological age, but this fact was not correlated with a greater presence of the risk allele ε4 or cognitive impairment. This is the first dataset of DNA methylation ages of a cohort of people with Down Syndrome in Latin America.

Psychological and biological resilience modulates the effects of stress on epigenetic aging

Our society is experiencing more stress than ever before, leading to both negative psychiatric and physical outcomes. Chronic stress is linked to negative long-term health consequences, raising the possibility that stress is related to accelerated aging. In this study, we examine whether resilience factors affect stress-associated biological age acceleration. Recently developed “epigenetic clocks” such as GrimAge have shown utility in predicting biological age and mortality. Here, we assessed the impact of cumulative stress, stress physiology, and resilience on accelerated aging in a community sample (N = 444). Cumulative stress was associated with accelerated GrimAge (P = 0.0388) and stress-related physiologic measures of adrenal sensitivity (Cortisol/ACTH ratio) and insulin resistance (HOMA). After controlling for demographic and behavioral factors, HOMA correlated with accelerated GrimAge (P = 0.0186). Remarkably, psychological resilience factors of emotion regulation and self-control moderated these relationships. Emotion regulation moderated the association between stress and aging (P = 8.82e−4) such that with worse emotion regulation, there was greater stress-related age acceleration, while stronger emotion regulation prevented any significant effect of stress on GrimAge. Self-control moderated the relationship between stress and insulin resistance (P = 0.00732), with high self-control blunting this relationship. In the final model, in those with poor emotion regulation, cumulative stress continued to predict additional GrimAge Acceleration even while accounting for demographic, physiologic, and behavioral covariates. These results demonstrate that cumulative stress is associated with epigenetic aging in a healthy population, and these associations are modified by biobehavioral resilience factors.