Epigenetic Biomarker Of Aging Research Articles

Circular RNAs as multifaceted molecular regulators of vital activity and potential biomarkers of aging.

Aging presents a significant challenge to health and social care systems due to the increasing proportion of the elderly population. The identification of reliable biomarkers to assess the progression of aging remains an unresolved question. Circular RNAs (circRNAs) are single-stranded covalently closed RNAs. They have been found to regulate various biological processes. CircRNAs are present in human biological fluids, are relatively stable, and accumulate with age, making them promising as biomarkers of aging. Current information on the expression of circRNAs in aging was analyzed using scientific databases. In this review, we have identified key stages in the study of circRNAs during aging and summarized the current understanding of their biogenesis. By focusing on the role of circRNAs in processes that contribute to aging - such as genomic stability, metabolism, cell death, and signaling pathways - we hypothesize that circRNAs may drive the aging process through their age-related accumulation and resultant deregulation. Examples of age-related differential expression of circRNAs in various species, including humans, are provided. This review highlights the importance of finding novel epigenetic biomarkers of aging, beyond the already identified molecules (circFOXO3, circRNA100783, circPVT1), and highlights circRNAs as a potential therapeutic target for the treatment of age-associated diseases.

Retro-age: A unique epigenetic biomarker of aging captured by DNA methylation states of retroelements.

Reactivation of retroelements in the human genome has been linked to aging. However, whether the epigenetic state of specific retroelements can predict chronological age remains unknown. We provide evidence that locus-specific retroelement DNA methylation can be used to create retroelement-based epigenetic clocks that accurately measure chronological age in the immune system, across human tissues, and pan-mammalian species. We also developed a highly accurate retroelement epigenetic clock compatible with EPICv.2.0 data that was constructed from CpGs that did not overlap with existing first- and second-generation epigenetic clocks, suggesting a unique signal for epigenetic clocks not previously captured. We found retroelement-based epigenetic clocks were reversed during transient epigenetic reprogramming, accelerated in people living with HIV-1, and responsive to antiretroviral therapy. Our findings highlight the utility of retroelement-based biomarkers of aging and support a renewed emphasis on the role of retroelements in geroscience.

Associations between epigenetic aging and diabetes mellitus in a Swedish longitudinal study

Diabetes mellitus type 2 (T2D) is associated with accelerated biological aging and the increased risk of onset of other age-related diseases. Epigenetic changes in DNA methylation levels have been found to serve as reliable biomarkers for biological aging. This study explores the relationship between various epigenetic biomarkers of aging and diabetes risk using longitudinal data. Data from the Swedish Adoption/Twin Study of Aging (SATSA) was collected from 1984 to 2014 and included 536 individuals with at least one epigenetic measurement. The following epigenetic biomarkers of aging were employed: DNAm PAI-1, DNAmTL, DunedinPACE, PCHorvath1, PCHorvath2, PCHannum, PCPhenoAge, and PCGrimAge. Firstly, longitudinal analysis of biomarker trajectories was done. Secondly, linear correlations between the biomarkers and time to diabetes were studied within individuals developing diabetes. Thirdly, Cox proportional hazards (PH) models were used to assess the associations between these biomarkers and time of diabetes diagnosis, with adjustments for chronological age, sex, education, smoking, blood glucose, and BMI. The longitudinal trajectories of the biomarkers revealed differences between individuals with and without diabetes. Smoothened average curves for DunedinPACE and DNAm PAI-1 were higher for individuals with diabetes around the age 60–70, compared to controls. Likewise, DunedinPACE and DNAm PAI-1 were higher closer to diabetes onset. However, no significant associations were found between the epigenetic biomarkers of aging and risk of diabetes in Cox PH models. Our findings suggest the potential value of developing epigenetic biomarkers specifically tailored to T2D, should we wish to model and explore the potential for predicting the disease.

Epigenome‐wide association study of Aβ42/Aβ40 in a sample of U.S. middle‐aged twins

AbstractBackgroundDNA methylation may affect expression of genes that promote the accumulation of amyloid‐β (Aβ). Although prior studies suggest that DNA methylation correlates with Aβ in older adults (Levine et al. (2018). An epigenetic biomarker of aging for lifespan and healthspan. Aging, 10(4), 573.), Aβ begins to accumulate earlier than when clinical symptoms associated with Aβ are evident. The purpose of the current study is to present novel results on whether differentially methylated CpG sites (i.e., regions of DNA where methylation occurs) correlate with higher Aβ42/Aβ40 ratios across a sample of middle‐aged individuals.MethodData from 193 individual twins from the Louisville Twin Study were used in the current analysis. Genomic DNA was extracted from venipuncture blood samples, and bisulfite‐converted DNA samples were assessed with the Illumina Infinium EpicArray BeadChip. Quality control and analyses were performed in R using the minfi package, and gene ontology analyses were performed using the MissMethyl package. Aβ42/Aβ40 was estimated using a capture sandwich immunoassay methodology that measures AD biomarkers in whole‐blood plasma. Differential DNA methylation was estimated using multivariable linear regression with an empirical Bayes estimator.ResultEstimation of differential DNA methylation was adequate (λ = 1.38), although some Type I inflation of p‐values was observed among CpG sites with higher p‐values. Although no CpG sites reached genome‐wide statistical significance, the top four CpG sites suggested differential methylation ranging between 2.8–4.8% per unit increase in the ratio of Aβ42/Aβ40. The top gene sets associated with differential methylation were response to glucocorticoids, response to corticosteroids, and response to Aβ.ConclusionDespite no statistically significant CpG probes identified, likely due to the small sample size, the findings from the gene ontology analysis suggest that identification of epigenetic biomarkers may clarify the biological pathways through which the epigenome may regulate expression of Aβ proteins. As data collection is ongoing, we expect detected of genome‐wide significant probes with larger sample sizes.

Associations between neighborhood socioeconomic deprivation, IFNγ, and high-density lipoprotein particle size: Data from the Washington, D.C. cardiovascular health and needs assessment

IntroductionNeighborhood socioeconomic deprivation is associated with increased cardiovascular risk factors, including inflammation. Inflammation plays an important role in modifying the cardioprotective function of high-density lipoprotein (HDL). Moreover, recent studies suggest that very high HDL is associated with adverse cardiovascular disease (CVD) outcomes. Thus, we sought to explore the relationships between neighborhood socioeconomic deprivation as a marker of chronic stress, inflammation, proprotein convertase subtilisin/kexin type 9 (PCSK9) (a core component of the HDL proteome), HDL characterisitcs, and biological aging as a predictor of CVD and all-cause mortality. MethodsSixty African American subjects were recruited to the NIH Clinical Center as part of a community-based participatory research-designed observational study. Neighborhood deprivation index (NDI), a marker of neighborhood socioeconomic deprivation, was measured using US Census data. HDL characteristics (cholesterol, particle number, size, subspecies) were determined from NMR lipoprotein profiling, and plasma cytokines (IL-1β, IL-6, IL-8, TNFα, IFNγ) were measured using an ELISA-based multiplex technique. Epigenetic clock biomarkers of aging were measured using DNA methylation data obtained from participants' buffy coat samples. We used linear regression modeling adjusted for atherosclerotic cardiovascular disease (ASCVD) risk score, body mass index (BMI), and lipid-lowering medication use to investigate relationships of interest. ResultsNDI directly associated with large HDL particle count (H7P) and IFNγ and trended toward significance with HDL-C and PCSK9. IFNγ and PCSK9 then directly associated with H7P. H7P also directly associated with higher DNA methylation phenotypic age (PhenoAge). ConclusionWe highlight associations between neighborhood socioeconomic deprivation, IFNγ, PCSK9, HDL subspecies, and epigenetic biomarkers of aging. Taken together, our findings suggest indirect pathways linking neighborhood deprivation-related stress and inflammation to HDL and immune epigenetic changes. Moreover, these results add to recent work showing the pathogenicity of high HDL levels and underscore the need to understand how chronic stress-related inflammation and lipoprotein subspecies relate to CVD risk across diverse populations.

Maternal and Paternal Dietary Quality and Dietary Inflammation Associations with Offspring DNA Methylation and Epigenetic Biomarkers of Aging in the Lifeways Cross-Generation Study

BackgroundEarly-life nutritional exposures may contribute to offspring epigenetic modifications. However, few studies have evaluated parental dietary quality effects on offspring DNA methylation (DNAm). ObjectivesWe aim to fill this gap by elucidating the influence of maternal and paternal whole-diet quality and inflammatory potential on offspring DNAm in the Lifeways Cross-generation cohort. MethodsFamilies (n = 1124) were recruited around 16 weeks of gestation in the Republic of Ireland between 2001 and 2003. Maternal dietary intake during the first trimester and paternal diet during the 12 previous months were assessed with an FFQ. Parental dietary inflammatory potential and quality were determined using the energy-adjusted Dietary Inflammatory Index (E-DII), the Healthy Eating Index-2015 (HEI-2015), and the maternal DASH score. DNAm in the saliva of 246 children at age nine was measured using the Illumina Infinium HumanMethylationEPIC array. DNAm-derived biomarkers of aging, the Pediatric-Buccal-Epigenetic clock and DNAm estimator of telomere length, were calculated. Parental diet associations with the DNAm concentrations of 850K Cytosine-phosphate-guanine sites (CpG sites) and with DNAm-derived biomarkers of aging were examined using an epigenome-wide association study and linear regressions, respectively. ResultsMaternal HEI-2015 scores were inversely associated with DNAm at CpG site (cg21840035) located near the PLEKHM1 gene, whose functions involve regulation of bone development (β = −0.0036, per 1 point increase in the score; P = 5.6 × 10−8). Higher paternal HEI-2015 score was related to lower methylation at CpG site (cg22431767), located near cell signaling gene LUZP1 (β = −0.0022, per 1 point increase in the score, P = 4.1 × 10−8). There were no associations with parental E-DII and DASH scores, and no evidence of major effects on biomarkers of aging. ConclusionsParental dietary quality in the prenatal period, evaluated by the HEI-2015, may influence offspring DNAm during childhood. Further research to improve our understanding of parental nutritional programming is warranted.

Epigenetic Predictors of Mortality and Neighborhood Disadvantage

BACKGROUND AND AIM: Neighborhood characteristics are strongly associated with mortality even in geographically restricted urban areas, i.e. within a single city. Accelerated epigenetic aging and mortality risk present a lens through which to quantify impacts of the neighborhood environment on health and wellness. These biomarkers may also be useful indicators of sensitivity to environmental METHODS: We examined associations between the built environment and epigenetic biomarkers of aging and mortality risk in an urban, majority Black population of Detroit, MI. Associations were adjusted for relevant confounders, evaluated in sex-stratified models, and examined for alteration by study participant's perception of their neighborhood. We examined greenspace as a possible beneficial neighborhood factor. In separate analyses, we examined if epigenetic aging biomarkers are indicators of sensitivity to air pollution in an urban population of central North Carolina. RESULTS:We observed significant associations between the built environment in each neighborhood and multiple epigenetic biomarkers of aging. These associations indicated that residence in disadvantaged neighborhoods accelerated the aging process and increased mortality risk. Associations were often stronger amongst women than men and were not impacted by individual neighborhood perception. Greenspace appeared to be a protective factor. In separate analyses, we observed that accelerated epigenetic aging increases health risks from traffic-related air pollution. CONCLUSIONS:Neighborhood environmental characteristics are determinants of longevity and this may be reflected in aging biomarkers. These biomarkers have the potential to serve as both early indicators of health deterioration and indicators of beneficial environmental interventions, such as increasing greenspace. As these biomarkers may also be indicators of elevated environmental health risks, they may be indicative of relationships between neighborhood environmental factors whereby negative built environmental factors accelerate epigenetic aging thereby increasing both mortality risks and sensitivity to other environmental exposures such as air pollution. This abstract does not necessarily represent EPA policy. KEYWORDS: built environment, epigenetics, disadvantaged neighborhoods, social determinants of health, epigenetic aging, mortality biomarkers

Accelerated epigenetic aging in adolescents living with HIV is associated with altered development of brain structures.

We recently demonstrated that adolescents perinatally infected with HIV-1 (PHIV+) have accelerated aging as measured by a highly accurate epigenetic biomarker of aging known as the epigenetic clock. However, whether epigenetic age acceleration in PHIV+ impacts brain development at the macro- and microstructural levels of brain anatomy has not been studied. We report on a cross-sectional study of PHIV+ enrolled in the Cape Town Adolescent Antiretroviral Cohort (CTAAC). The Illumina Infinium Methylation EPIC array was used to generate DNA methylation data from the blood samples of 180 PHIV+ aged 9 to 12years. The epigenetic clock software and method was used to estimate two measures, epigenetic age acceleration (AgeAccelerationResidual) and extrinsic epigenetic age acceleration (EEAA). Each participant underwent T1 structural magnetic resonance imaging (MRI) and diffusion tensor imaging (DTI). In order to investigate the associations of chronological age, sex, epigenetic age acceleration and treatment variables (CNS penetration effectiveness score (CPE)) of antiretroviral regimen on brain structure in PHIV+, we developed stepwise multiple regression models in R (version 3.4.3, 2017) including grey and white matter volumes, cortical thickness, cortical surface area and DTI measures of white matter microstructural integrity. The mean DNAm age (16.01years) of the participants was higher than their mean chronological age (10.77years). Epigenetic age acceleration contributed more to regional alterations of brain volumes, cortical thickness, cortical surface areas and neuronal microstructure than chronological age, in a range of regions. CPE positively contributed to volume of the brain stem. Understanding the drivers of epigenetic age acceleration could lead to valuable insights into structural brain alterations, and the persistence of neurocognitive disorders in seen in PHIV+ .

Accelerated epigenetic aging in adolescents from low-income households is associated with altered development of brain structures.

The relationship between cognitive performance, macro and microstructural brain anatomy and accelerated aging as measured by a highly accurate epigenetic biomarker of aging known as the epigenetic clock in healthy adolescents has not been studied. Healthy adolescents enrolled in the Cape Town Adolescent Antiretroviral Cohort Study were studied cross sectionally. The Illumina Infinium Methylation EPIC array was used to generate DNA methylation data from the blood samples of 44 adolescents aged 9 to 12years old. The epigenetic clock software and method was used to estimate two measures, epigenetic age acceleration residual (AAR) and extrinsic epigenetic age acceleration (EEAA). Each participant underwent neurocognitive testing, T1 structural magnetic resonance imaging (MRI), and diffusion tensor imaging (DTI). Correlation tests were run between the two epigenetic aging measures and 10 cognitive functioning domains, to assess for differences in cognitive performance as epigenetic aging increases. In order to investigate the associations of epigenetic age acceleration on brain structure, we developed stepwise multiple regression models in R (version 3.4.3, 2017) including grey and white matter volumes, cortical thickness, and cortical surface area, as well as DTI measures of white matter microstructural integrity. In addition to negatively affecting two cognitive domains, visual memory (p = .026) and visual spatial acuity (p = .02), epigenetic age acceleration was associated with alterations of brain volumes, cortical thickness, cortical surface areas and abnormalities in neuronal microstructure in a range of regions. Stress was a significant predictor (p = .029) of AAR. Understanding the drivers of epigenetic age acceleration in adolescents could lead to valuable insights into the development of neurocognitive impairment in adolescents.

Abstract P272: Associations of an Epigenetic Biomarker of Aging and Healthspan With BMI Status and Metabolic Health in Adult African Americans: The Atherosclerosis Risk in Communities (ARIC) Study

Introduction: Individuals with obesity are thought to be protected against some chronic disease as long as they do not incur metabolic health (MH) conditions. A new epigenetic biomarker of accelerated biological aging and health span, PhenoAge, was developed using DNA methylation (DNAm) markers. We hypothesized that obesity would be associated with higher PhenoAge than normal weight and overweight individuals only in the presence of MH conditions. Methods: DNAm was measured in leukocyte DNA for 2,454 African American participants (mean age=56.4 years) and used to calculate PhenoAge. BMI status was categorized as normal weight, overweight, and obese and MH was categorized by 0, 1, or at least 2 of the following: coronary heart disease, stroke, hypertension, type-2 diabetes, and hyperlipidemia. Linear regression tested the cross-sectional association of PhenoAge with BMI and MH, adjusting for sociodemographic variables, smoking, and technical variables. Stratified analyses by MH status were conducted to illustrate the statistical effects of BMI status in adults with and without MH conditions. Results: Participants with obesity had approximately 8 months higher PhenoAge compared to normal weight (β=0.68, 95% CI=0.21, 1.14, p=4.1E-3), and those with one (β=0.55, 95% CI=0.15, 0.94, p=6.4E-3) or at least 2 (β=0.81, 95% CI=0.38, 1.25, p=2E-4) MH conditions also had higher PhenoAge compared to those with 0 conditions. Figure 1 shows increments in PhenoAge with increments in number of MH conditions regardless of BMI. PhenoAge was significantly higher for obese compared to overweight for 0 and 1 MH conditions, but not compared to normal weight. Conclusions: In African American adults, both obesity status and presence of MH conditions were associated with a higher PhenoAge, suggesting metabolically healthy obesity is not entirely benign. Further phenotyping of the “metabolic health” obese condition is warranted to understand its relevance for healthspan.

Abstract 002: Adherence to Ideal Life’s Simple 7 Metrics is Associated With Epigenetic Biomarkers of Aging in African Americans: The Atherosclerosis Risk in Communities (ARIC) Study

Introduction: DNA methylation age acceleration (DNAmAA) scores, which are epigenetic biomarkers of aging and physiological responses to environmental factors such as lifestyle and health behaviors, have been previously shown to be associated with cardiovascular disease (CVD) outcomes and all-cause mortality. Life’s Simple 7 (LS7) is a tool promoted by the American Heart Association that summarizes individual adherence to seven key cardiovascular health and lifestyle metrics. We hypothesized that greater LS7 adherence would be associated with lower DNAmAA, consistent with slower biological aging. Methods: Associations between DNAmAA and LS7 were estimated separately in 2,312 African American (AA) and 1,036 European American (EA) adult participants in the Atherosclerosis Risk in Communities (ARIC) study. Visit 1 (mean age = 53 yrs in AA adults, 56 yrs in EA adults) LS7 was calculated for each participant, with 0, 1, or 2 points assigned by adherence to each component: smoking status, body mass index, physical activity, diet, plasma cholesterol, blood pressure, and fasting glucose . The summed score was categorized as inadequate (0-4), intermediate (5-9), or ideal (10-14) LS7 status. Three different previously published DNAmAA scores (Horvath, Hannum, and PhenoAge), were calculated using data from the Illumina HM450K BeadChip on stored frozen leukocytes available at visit 2 or 3 (approximately 3-6 years later). Linear regression models tested the association of LS7 category with DNAm scores, adjusting for sex, chronological age, education, income, study center, alcohol use , white blood cell count , imputed WBC type proportions using the Houseman method, Illumina HumanExome Beadchip principal components for genetic ancestry , and Illumina HM450K control probe principal components for technical adjustment. The Bonferonni-corrected threshold for statistical significance across the six tests was set to p<0.0083 (0.05/6). Results: Among AA adults, ideal LS7 status (compared to poor status) was associated with a 1 year lower PhenoAge acceleration (β=-1.03; 95%CI=-1.70, -0.35; p=0.003), but was not significantly associated with Horvath or Hannum DNAmAA scores. In EA adults, ideal LS7 adherence was not significantly associated with any of the three DNAmAA scores, but the direction and magnitude of the PhenoAge acceleration association in EA was similar to that in AA (β=-0.96; 95%CI=-2.66, 0.73; p=0.27). Conclusions: African American adults with ideal LS7 status had lower PhenoAge acceleration than African Americans who did not, suggesting that heart-healthy lifestyles may slow biological aging processes in this population. Future studies should examine the prospective associations of changes in healthy lifestyle and changes in epigenetic biomarkers of aging as well as modifiers of this relationship.

AN EPIGENETIC CLOCK FOR AGING AND LIFE EXPECTANCY

While the first generation of epigenetic biomarkers of aging were developed using chronological age as a surrogate for biological age, we hypothesize that incorporation of clinical measures of “phenotypic age” may facilitate the development of a more powerful epigenetic biomarker of aging. Results show that our newly developed epigenetic biomarker of aging strongly outperforms previous measures, in regards to predictions for a variety of aging outcomes-all-cause mortality, cancers, physical functioning, and Alzheimer’s disease. Additionally, while this biomarker was developed using data from whole blood, it strongly predicts age in every tissue and cell tested. Finally, transcriptional analysis points to the potential role of interferon signaling, transcriptional machinery, and DNA damage signaling. Overall, this single epigenetic biomarker of aging is able to capture risks for an array of diverse outcomes across multiple tissues and cells, and may facilitate the development of interventions aimed at increasing healthy life expectancy.

Perinatally acquired HIV infection accelerates epigenetic aging in South African adolescents.

Recent studies demonstrate that infection with the HIV-1 is associated with accelerated aging effects in adults according to a highly accurate epigenetic biomarker of aging known as epigenetic clock. However, it is not yet known whether epigenetic age acceleration occurs as early as adolescence in perinatally HIV-infected (PHIV+) youth. Observational study of PHIV and HIV-uninfected adolescents enrolled in the Cape Town Adolescent Antiretroviral Cohort Study. The Illumina EPIC array was used to generate blood DNA methylation data from 204 PHIV and 44 age-matched, uninfected (HIV-) adolescents aged 9-12 years old. The epigenetic clock software and method was used to estimate two measures of epigenetic age acceleration. Each participant completed a comprehensive neuropsychological test battery upon enrollment to Cape Town Adolescent Antiretroviral Cohort. HIV is associated with biologically older blood in PHIV+ adolescents according to both measures of epigenetic age acceleration. One of the measures, extrinsic epigenetic age acceleration, is negatively correlated with measures of cognitive functioning (executive functioning, working memory, processing speed). Overall, our results indicate that epigenetic age acceleration in blood can be observed in PHIV+ adolescents and that these epigenetic changes accompany poorer cognitive functioning.

An epigenetic biomarker of aging for lifespan and healthspan.

Identifying reliable biomarkers of aging is a major goal in geroscience. While the first generation of epigenetic biomarkers of aging were developed using chronological age as a surrogate for biological age, we hypothesized that incorporation of composite clinical measures of phenotypic age that capture differences in lifespan and healthspan may identify novel CpGs and facilitate the development of a more powerful epigenetic biomarker of aging. Using an innovative two-step process, we develop a new epigenetic biomarker of aging, DNAm PhenoAge, that strongly outperforms previous measures in regards to predictions for a variety of aging outcomes, including all-cause mortality, cancers, healthspan, physical functioning, and Alzheimer's disease. While this biomarker was developed using data from whole blood, it correlates strongly with age in every tissue and cell tested. Based on an in-depth transcriptional analysis in sorted cells, we find that increased epigenetic, relative to chronological age, is associated with increased activation of pro-inflammatory and interferon pathways, and decreased activation of transcriptional/translational machinery, DNA damage response, and mitochondrial signatures. Overall, this single epigenetic biomarker of aging is able to capture risks for an array of diverse outcomes across multiple tissues and cells, and provide insight into important pathways in aging.

Maintenance of age in human neurons generated by microRNA-based neuronal conversion of fibroblasts

Aging is a major risk factor in many forms of late-onset neurodegenerative disorders. The ability to recapitulate age-related characteristics of human neurons in culture will offer unprecedented opportunities to study the biological processes underlying neuronal aging. Here, we show that using a recently demonstrated microRNA-based cellular reprogramming approach, human fibroblasts from postnatal to near centenarian donors can be efficiently converted into neurons that maintain multiple age-associated signatures. Application of an epigenetic biomarker of aging (referred to as epigenetic clock) to DNA methylation data revealed that the epigenetic ages of fibroblasts were highly correlated with corresponding age estimates of reprogrammed neurons. Transcriptome and microRNA profiles reveal genes differentially expressed between young and old neurons. Further analyses of oxidative stress, DNA damage and telomere length exhibit the retention of age-associated cellular properties in converted neurons from corresponding fibroblasts. Our results collectively demonstrate the maintenance of age after neuronal conversion.

An epigenetic clock analysis of race/ethnicity, sex, and coronary heart disease.

BackgroundEpigenetic biomarkers of aging (the “epigenetic clock”) have the potential to address puzzling findings surrounding mortality rates and incidence of cardio-metabolic disease such as: (1) women consistently exhibiting lower mortality than men despite having higher levels of morbidity; (2) racial/ethnic groups having different mortality rates even after adjusting for socioeconomic differences; (3) the black/white mortality cross-over effect in late adulthood; and (4) Hispanics in the United States having a longer life expectancy than Caucasians despite having a higher burden of traditional cardio-metabolic risk factors.ResultsWe analyzed blood, saliva, and brain samples from seven different racial/ethnic groups. We assessed the intrinsic epigenetic age acceleration of blood (independent of blood cell counts) and the extrinsic epigenetic aging rates of blood (dependent on blood cell counts and tracks the age of the immune system). In blood, Hispanics and Tsimane Amerindians have lower intrinsic but higher extrinsic epigenetic aging rates than Caucasians. African-Americans have lower extrinsic epigenetic aging rates than Caucasians and Hispanics but no differences were found for the intrinsic measure. Men have higher epigenetic aging rates than women in blood, saliva, and brain tissue.ConclusionsEpigenetic aging rates are significantly associated with sex, race/ethnicity, and to a lesser extent with CHD risk factors, but not with incident CHD outcomes. These results may help elucidate lower than expected mortality rates observed in Hispanics, older African-Americans, and women.Electronic supplementary materialThe online version of this article (doi:10.1186/s13059-016-1030-0) contains supplementary material, which is available to authorized users.

Genetic variants near MLST8 and DHX57 affect the epigenetic age of the cerebellum

DNA methylation (DNAm) levels lend themselves for defining an epigenetic biomarker of aging known as the ‘epigenetic clock'. Our genome-wide association study (GWAS) of cerebellar epigenetic age acceleration identifies five significant (P<5.0 × 10−8) SNPs in two loci: 2p22.1 (inside gene DHX57) and 16p13.3 near gene MLST8 (a subunit of mTOR complex 1 and 2). We find that the SNP in 16p13.3 has a cis-acting effect on the expression levels of MLST8 (P=6.9 × 10−18) in most brain regions. In cerebellar samples, the SNP in 2p22.1 has a cis-effect on DHX57 (P=4.4 × 10−5). Gene sets found by our GWAS analysis of cerebellar age acceleration exhibit significant overlap with those of Alzheimer's disease (P=4.4 × 10−15), age-related macular degeneration (P=6.4 × 10−6), and Parkinson's disease (P=2.6 × 10−4). Overall, our results demonstrate the utility of a new paradigm for understanding aging and age-related diseases: it will be fruitful to use epigenetic tissue age as endophenotype in GWAS.

Infant's DNA Methylation Age at Birth and Epigenetic Aging Accelerators.

Knowing the biological age of the neonates enables us to evaluate and better understand the health and maturity comprehensively. However, because of dearth of biomarkers, it is difficult to quantify the neonatal biological age. Here we sought to quantify and assess the variability in biological age at birth and to better understand how the aging rates before birth are influenced by exposure in intrauterine period by employing a novel epigenetic biomarker of aging (epigenetic clock). We observed that the methylation age at birth was independent of the infant's sex but was significantly influenced by race. Partial correlation analysis showed a significant negative relationship between maternal socioeconomic status and infants' methylation age (r s = −0.48, P s = 0.005). A significant association with the risk of fast aging was observed for prenatal exposure to tobacco smoke with OR (95% CI) of 3.17 (1.05–9.56). Both estimated cell abundance measures and lymphocyte subpopulations in cord blood showed that tobacco exposed group exhibit an altered T cell compartment, specifically substantial loss of naive T cells. Present study provides the first evidence that common perinatal exposure (such as maternal smoking and lower socioeconomic status) may be important aging accelerators and substantial loss of naive T cells may play a role in the smoking-related fast aging phenomenon.

HIV-1 Infection Accelerates Age According to the Epigenetic Clock

Background. Infection with human immunodeficiency virus type 1 (HIV) is associated with clinical symptoms of accelerated aging, as evidenced by the increased incidence and diversity of age-related illnesses at relatively young ages and supporting findings of organ and cellular pathologic analyses. But it has been difficult to detect an accelerated aging effect at a molecular level.Methods. Here, we used an epigenetic biomarker of aging based on host DNA methylation levels to study accelerated aging effects due to HIV infection. DNA from brain and blood tissue was assayed via the Illumina Infinium Methylation 450 K platform.Results. Using 6 novel DNA methylation data sets, we show that HIV infection leads to an increase in epigenetic age both in brain tissue (7.4 years) and blood (5.2 years). While the observed accelerated aging effects in blood may reflect changes in blood cell composition (notably exhausted cytotoxic T cells), it is less clear what explains the observed accelerated aging effects in brain tissue.Conclusions. Overall, our results demonstrate that the epigenetic clock is a useful biomarker for detecting accelerated aging effects due to HIV infection. This tool can be used to accurately determine the extent of age acceleration in individual tissues and cells.

Impact of age, BMI and HbA1c levels on the genome-wide DNA methylation and mRNA expression patterns in human adipose tissue and identification of epigenetic biomarkers in blood

Increased age, BMI and HbA1c levels are risk factors for several non-communicable diseases. However, the impact of these factors on the genome-wide DNA methylation pattern in human adipose tissue remains unknown. We analyzed the DNA methylation of ∼480 000 sites in human adipose tissue from 96 males and 94 females and related methylation to age, BMI and HbA1c. We also compared epigenetic signatures in adipose tissue and blood. Age was significantly associated with both altered DNA methylation and expression of 1050 genes (e.g. FHL2, NOX4 and PLG). Interestingly, many reported epigenetic biomarkers of aging in blood, including ELOVL2, FHL2, KLF14 and GLRA1, also showed significant correlations between adipose tissue DNA methylation and age in our study. The most significant association between age and adipose tissue DNA methylation was found upstream of ELOVL2. We identified 2825 genes (e.g. FTO, ITIH5, CCL18, MTCH2, IRS1 and SPP1) where both DNA methylation and expression correlated with BMI. Methylation at previously reported HIF3A sites correlated significantly with BMI in females only. HbA1c (range 28-46 mmol/mol) correlated significantly with the methylation of 711 sites, annotated to, for example, RAB37, TICAM1 and HLA-DPB1. Pathway analyses demonstrated that methylation levels associated with age and BMI are overrepresented among genes involved in cancer, type 2 diabetes and cardiovascular disease. Our results highlight the impact of age, BMI and HbA1c on epigenetic variation of candidate genes for obesity, type 2 diabetes and cancer in human adipose tissue. Importantly, we demonstrate that epigenetic biomarkers in blood can mirror age-related epigenetic signatures in target tissues for metabolic diseases such as adipose tissue.