scholarly journals DNAm-based signatures of accelerated aging and mortality in blood are associated with low renal function

2021 ◽  
Vol 13 (1) ◽  
Author(s):  
Pamela R. Matías-García ◽  
Cavin K. Ward-Caviness ◽  
Laura M. Raffield ◽  
Xu Gao ◽  
Yan Zhang ◽  
...  
Keyword(s):  
Dna Methylation ◽  
African American ◽  
Kidney Disease ◽  
Meta Analysis ◽  
Methylation Status ◽  
Serum Urate ◽  
Biological Aging ◽  
Epigenetic Biomarkers ◽  
Age Related ◽  
New Findings

Abstract Background The difference between an individual's chronological and DNA methylation predicted age (DNAmAge), termed DNAmAge acceleration (DNAmAA), can capture life-long environmental exposures and age-related physiological changes reflected in methylation status. Several studies have linked DNAmAA to morbidity and mortality, yet its relationship with kidney function has not been assessed. We evaluated the associations between seven DNAm aging and lifespan predictors (as well as GrimAge components) and five kidney traits (estimated glomerular filtration rate [eGFR], urine albumin-to-creatinine ratio [uACR], serum urate, microalbuminuria and chronic kidney disease [CKD]) in up to 9688 European, African American and Hispanic/Latino individuals from seven population-based studies. Results We identified 23 significant associations in our large trans-ethnic meta-analysis (p < 1.43E−03 and consistent direction of effect across studies). Age acceleration measured by the Extrinsic and PhenoAge estimators, as well as Zhang’s 10-CpG epigenetic mortality risk score (MRS), were associated with all parameters of poor kidney health (lower eGFR, prevalent CKD, higher uACR, microalbuminuria and higher serum urate). Six of these associations were independently observed in European and African American populations. MRS in particular was consistently associated with eGFR (β =  − 0.12, 95% CI = [− 0.16, − 0.08] change in log-transformed eGFR per unit increase in MRS, p = 4.39E−08), prevalent CKD (odds ratio (OR) = 1.78 [1.47, 2.16], p = 2.71E-09) and higher serum urate levels (β = 0.12 [0.07, 0.16], p = 2.08E−06). The “first-generation” clocks (Hannum, Horvath) and GrimAge showed different patterns of association with the kidney traits. Three of the DNAm-estimated components of GrimAge, namely adrenomedullin, plasminogen-activation inhibition 1 and pack years, were positively associated with higher uACR, serum urate and microalbuminuria. Conclusion DNAmAge acceleration and DNAm mortality predictors estimated in whole blood were associated with multiple kidney traits, including eGFR and CKD, in this multi-ethnic study. Epigenetic biomarkers which reflect the systemic effects of age-related mechanisms such as immunosenescence, inflammaging and oxidative stress may have important mechanistic or prognostic roles in kidney disease. Our study highlights new findings linking kidney disease to biological aging, and opportunities warranting future investigation into DNA methylation biomarkers for prognostic or risk stratification in kidney disease.

scholarly journals Regular, Intense Exercise Training as a Healthy Aging Lifestyle Strategy: Preventing DNA Damage, Telomere Shortening and Adverse DNA Methylation Changes Over a Lifetime

2021 ◽  
Vol 12 ◽  
Author(s):  
Maha Sellami ◽  
Nicola Bragazzi ◽  
Mohammad Shoaib Prince ◽  
Joshua Denham ◽  
Mohamed Elrayess
Keyword(s):  
Dna Methylation ◽  
Dna Damage ◽  
Exercise Training ◽  
Epigenetic Modification ◽  
Methylation Status ◽  
The Body ◽  
Training Load ◽  
Activity Level ◽  
Biological Aging ◽  
Age Related

Exercise training is one of the few therapeutic interventions that improves health span by delaying the onset of age-related diseases and preventing early death. The length of telomeres, the 5′-TTAGGGn-3′ tandem repeats at the ends of mammalian chromosomes, is one of the main indicators of biological age. Telomeres undergo shortening with each cellular division. This subsequently leads to alterations in the expression of several genes that encode vital proteins with critical functions in many tissues throughout the body, and ultimately impacts cardiovascular, immune and muscle physiology. The sub-telomeric DNA is comprised of heavily methylated, heterochromatin. Methylation and histone acetylation are two of the most well-studied examples of the epigenetic modifications that occur on histone proteins. DNA methylation is the type of epigenetic modification that alters gene expression without modifying gene sequence. Although diet, genetic predisposition and a healthy lifestyle seem to alter DNA methylation and telomere length (TL), recent evidence suggests that training status or physical fitness are some of the major factors that control DNA structural modifications. In fact, TL is positively associated with cardiorespiratory fitness, physical activity level (sedentary, active, moderately trained, or elite) and training intensity, but is shorter in over-trained athletes. Similarly, somatic cells are vulnerable to exercise-induced epigenetic modification, including DNA methylation. Exercise-training load, however, depends on intensity and volume (duration and frequency). Training load-dependent responses in genomic profiles could underpin the discordant physiological and physical responses to exercise. In the current review, we will discuss the role of various forms of exercise training in the regulation of DNA damage, TL and DNA methylation status in humans, to provide an update on the influence exercise training has on biological aging.

scholarly journals A Systematic Review and Meta-analysis of Environmental, Lifestyle, and Health Factors Associated With DNA Methylation Age

2019 ◽  
Vol 75 (3) ◽  
pp. 481-494 ◽  
Author(s):  
Joanne Ryan ◽  
Jo Wrigglesworth ◽  
Jun Loong ◽  
Peter D Fransquet ◽  
Robyn L Woods
Keyword(s):  
Dna Methylation ◽  
Meta Analysis ◽  
Conclusive Evidence ◽  
Chronological Age ◽  
Biological Aging ◽  
Robust Estimate ◽  
Healthy Life ◽  
Age Related ◽  
Health Factors ◽  
Dna Methylation Age

Abstract DNA methylation (DNAm) algorithms of biological age provide a robust estimate of an individual’s chronological age and can predict their risk of age-related disease and mortality. This study reviewed the evidence that environmental, lifestyle and health factors are associated with the Horvath and Hannum epigenetic clocks. A systematic search identified 61 studies. Chronological age was correlated with DNAm age in blood (median .83, range .13–.99). In a meta-analysis body mass index (BMI) was associated with increased DNAm age (Hannum β: 0.07, 95% CI 0.04 to 0.10; Horvath β: 0.06, 95% CI 0.02 to 0.10), but there was no association with smoking (Hannum β: 0.12, 95% CI −0.50 to 0.73; Horvath β:0.18, 95% CI −0.10 to 0.46). DNAm age was positively associated with frailty (three studies, n = 3,093), and education was negatively associated with the Hannum estimate of DNAm age specifically (four studies, n = 13,955). For most other exposures, findings were too inconsistent to draw conclusions. In conclusion, BMI was positively associated with biological aging measured using DNAm, with some evidence that frailty also increased aging. More research is needed to provide conclusive evidence regarding other exposures. This field of research has the potential to provide further insights into how to promote slower biological aging and ultimately prolong healthy life.

scholarly journals DNA methylation differs extensively between strains of the same geographical origin and changes with age in Daphnia magna

2021 ◽  
Vol 14 (1) ◽  
Author(s):  
Jack Hearn ◽  
Fiona Plenderleith ◽  
Tom J. Little
Keyword(s):  
Dna Methylation ◽  
Caloric Restriction ◽  
Daphnia Magna ◽  
Single Gene ◽  
Methylation Status ◽  
Strain Differences ◽  
Life History Trait ◽  
Food Level ◽  
Epigenetic Clock ◽  
Age Related

Abstract Background Patterns of methylation influence lifespan, but methylation and lifespan may also depend on diet, or differ between genotypes. Prior to this study, interactions between diet and genotype have not been explored together to determine their influence on methylation. The invertebrate Daphnia magna is an excellent choice for testing the epigenetic response to the environment: parthenogenetic offspring are identical to their siblings (making for powerful genetic comparisons), they are relatively short lived and have well-characterised inter-strain life-history trait differences. We performed a survival analysis in response to caloric restriction and then undertook a 47-replicate experiment testing the DNA methylation response to ageing and caloric restriction of two strains of D. magna. Results Methylated cytosines (CpGs) were most prevalent in exons two to five of gene bodies. One strain exhibited a significantly increased lifespan in response to caloric restriction, but there was no effect of food-level CpG methylation status. Inter-strain differences dominated the methylation experiment with over 15,000 differently methylated CpGs. One gene, Me31b, was hypermethylated extensively in one strain and is a key regulator of embryonic expression. Sixty-one CpGs were differentially methylated between young and old individuals, including multiple CpGs within the histone H3 gene, which were hypermethylated in old individuals. Across all age-related CpGs, we identified a set that are highly correlated with chronological age. Conclusions Methylated cytosines are concentrated in early exons of gene sequences indicative of a directed, non-random, process despite the low overall DNA methylation percentage in this species. We identify no effect of caloric restriction on DNA methylation, contrary to our previous results, and established impacts of caloric restriction on phenotype and gene expression. We propose our approach here is more robust in invertebrates given genome-wide CpG distributions. For both strain and ageing, a single gene emerges as differentially methylated that for each factor could have widespread phenotypic effects. Our data showed the potential for an epigenetic clock at a subset of age positions, which is exciting but requires confirmation.

scholarly journals DNA methylome signatures of prenatal exposure to synthetic glucocorticoids in hippocampus and peripheral whole blood of female guinea pigs in early life

2021 ◽  
Vol 11 (1) ◽  
Author(s):  
Aya Sasaki ◽  
Margaret E. Eng ◽  
Abigail H. Lee ◽  
Alisa Kostaki ◽  
Stephen G. Matthews
Keyword(s):  
Dna Methylation ◽  
Whole Blood ◽  
Guinea Pigs ◽  
Critical Role ◽  
Methylation Status ◽  
Peripheral Tissues ◽  
Epigenetic Biomarkers ◽  
Differentially Methylated Genes ◽  
Increased Risk ◽  
Synthetic Glucocorticoids

AbstractSynthetic glucocorticoids (sGC) are administered to women at risk of preterm delivery, approximately 10% of all pregnancies. In animal models, offspring exposed to elevated glucocorticoids, either by administration of sGC or endogenous glucocorticoids as a result of maternal stress, show increased risk of developing behavioral, endocrine, and metabolic dysregulation. DNA methylation may play a critical role in long-lasting programming of gene regulation underlying these phenotypes. However, peripheral tissues such as blood are often the only accessible source of DNA for epigenetic analyses in humans. Here, we examined the hypothesis that prenatal sGC administration alters DNA methylation signatures in guinea pig offspring hippocampus and whole blood. We compared these signatures across the two tissue types to assess epigenetic biomarkers of common molecular pathways affected by sGC exposure. Guinea pigs were treated with sGC or saline in late gestation. Genome-wide modifications of DNA methylation were analyzed at single nucleotide resolution using reduced representation bisulfite sequencing in juvenile female offspring. Results indicate that there are tissue-specific as well as common methylation signatures of prenatal sGC exposure. Over 90% of the common methylation signatures associated with sGC exposure showed the same directionality of change in methylation. Among differentially methylated genes, 134 were modified in both hippocampus and blood, of which 61 showed methylation changes at identical CpG sites. Gene pathway analyses indicated that prenatal sGC exposure alters the methylation status of gene clusters involved in brain development. These data indicate concordance across tissues of epigenetic programming in response to alterations in glucocorticoid signaling.

scholarly journals Meta-analysis of genome-wide DNA methylation and integrative OMICs in human skeletal muscle

2020 ◽  
Author(s):  
S Voisin ◽  
M Jacques ◽  
S Landen ◽  
NR Harvey ◽  
LM Haupt ◽  
...  
Keyword(s):  
Skeletal Muscle ◽  
Dna Methylation ◽  
Large Scale ◽  
Human Skeletal Muscle ◽  
Meta Analysis ◽  
Total N ◽  
Age Related ◽  
Differentially Methylated Genes ◽  
Comprehensive Picture ◽  
User Friendly

AbstractKnowledge of age-related DNA methylation changes in skeletal muscle is limited, yet this tissue is severely affected by aging in humans. Using a large-scale epigenome-wide association study (EWAS) meta-analysis of age in human skeletal muscle from 10 studies (total n = 908 human muscle methylomes), we identified 9,986 differentially methylated regions at a stringent false discovery rate < 0.005, spanning 8,748 unique genes, many of which related to skeletal muscle structure and development. We then integrated the DNA methylation results with known transcriptomic and proteomic age-related changes in skeletal muscle, and found that even though most differentially methylated genes are not altered at the mRNA or protein level, they are nonetheless strongly enriched for genes showing age-related differential expression. We provide here the most comprehensive picture of DNA methylation aging in human skeletal muscle, and have made our results available as an open-access, user-friendly, web-based tool called MetaMeth (https://sarah-voisin.shinyapps.io/MetaMeth/).

scholarly journals DNA Methylation of PI3K/AKT Pathway-Related Genes Predicts Outcome in Patients with Pancreatic Cancer: A Comprehensive Bioinformatics-Based Study

Cancers ◽  
2021 ◽  
Vol 13 (24) ◽  
pp. 6354
Author(s):  
Inês Faleiro ◽  
Vânia Palma Roberto ◽  
Secil Demirkol Canli ◽  
Nicolas A. Fraunhoffer ◽  
Juan Iovanna ◽  
...  
Keyword(s):  
Pancreatic Cancer ◽  
Dna Methylation ◽  
Methylation Status ◽  
Therapeutic Targets ◽  
The Cancer Genome Atlas ◽  
Prognostic Indicators ◽  
Diagnostic Tools ◽  
Akt Pathway ◽  
Epigenetic Alterations ◽  
Epigenetic Biomarkers

Pancreatic cancer (PCA) is one of the most lethal malignancies worldwide with a 5-year survival rate of 9%. Despite the advances in the field, the need for an earlier detection and effective therapies is paramount. PCA high heterogeneity suggests that epigenetic alterations play a key role in tumour development. However, only few epigenetic biomarkers or therapeutic targets have been identified so far. Here we explored the potential of distinct DNA methylation signatures as biomarkers for early detection and prognosis of PCA. PI3K/AKT-related genes differentially expressed in PCA were identified using the Pancreatic Expression Database (n = 153). Methylation data from PCA patients was obtained from The Cancer Genome Atlas (n = 183), crossed with clinical data to evaluate the biomarker potential of the epigenetic signatures identified and validated in independent cohorts. The majority of selected genes presented higher expression and hypomethylation in tumour tissue. The methylation signatures of specific genes in the PI3K/AKT pathway could distinguish normal from malignant tissue at initial disease stages with AUC > 0.8, revealing their potential as PCA diagnostic tools. ITGA4, SFN, ITGA2, and PIK3R1 methylation levels could be independent prognostic indicators of patients’ survival. Methylation status of SFN and PIK3R1 were also associated with disease recurrence. Our study reveals that the methylation levels of PIK3/AKT genes involved in PCA could be used to diagnose and predict patients’ clinical outcome with high sensitivity and specificity. These results provide new evidence of the potential of epigenetic alterations as biomarkers for disease screening and management and highlight possible therapeutic targets.

Individual DNA Methylation Profile is Correlated with Age and can be Targeted to Modulate Healthy Aging and Longevity

2019 ◽  
Vol 25 (39) ◽  
pp. 4139-4149 ◽  
Author(s):  
Francesco Guarasci ◽  
Patrizia D'Aquila ◽  
Alberto Montesanto ◽  
Andrea Corsonello ◽  
Dina Bellizzi ◽  
...  
Keyword(s):  
Dna Methylation ◽  
Mitochondrial Dna ◽  
Aging Process ◽  
Healthy Aging ◽  
Nuclear Dna ◽  
Epigenetic Modification ◽  
Biological Aging ◽  
Biomarkers Of Aging ◽  
Age Related

: Patterns of DNA methylation, the best characterized epigenetic modification, are modulated by aging. In humans, different studies at both site-specific and genome-wide levels have reported that modifications of DNA methylation are associated with the chronological aging process but also with the quality of aging (or biological aging), providing new perspectives for establishing powerful biomarkers of aging. : In this article, the role of DNA methylation in aging and longevity has been reviewed by analysing literature data about DNA methylation variations occurring during the lifetime in response to environmental factors and genetic background, and their association with the aging process and, in particular, with the quality of aging. Special attention has been devoted to the relationship between nuclear DNA methylation patterns, mitochondrial DNA epigenetic modifications, and longevity. Mitochondrial DNA has recently been reported to modulate global DNA methylation levels of the nuclear genome during the lifetime, and, in spite of the previous belief, it has been found to be the target of methylation modifications. : Analysis of DNA methylation profiles across lifetime shows that a remodeling of the methylome occurs with age and/or with age-related decline. Thus, it can be an excellent biomarker of aging and of the individual decline and frailty status. The knowledge about the mechanisms underlying these modifications is crucial since it might allow the opportunity for targeted treatment to modulate the rate of aging and longevity.

Abstract P271: Dna Methylation Measures of Aging in Midlife are Associated With Frailty Components in African American and European American Older Adults: The Atherosclerosis Risk in Communities (ARIC) Study

Circulation ◽  
2020 ◽  
Vol 141 (Suppl_1) ◽  
Author(s):  
Steven Nguyen ◽  
Weihua Guan ◽  
Jan Bressler ◽  
Megan Grove ◽  
Priya Palta ◽  
...  
Keyword(s):  
Physical Activity ◽  
Dna Methylation ◽  
Weight Loss ◽  
African American ◽  
Grip Strength ◽  
Late Life ◽  
Component Model ◽  
Biological Aging ◽  
European American ◽  
Frailty Status

Introduction: Several putative biomarkers of accelerated biological aging have been developed from patterns of DNA methylation in blood and other tissues (DNAm-Age scores). Some of these DNAm-Age scores have been found to be associated with age-related outcomes such as CVD and all-cause mortality, but their associations with frailty are unclear. We hypothesized that higher DNAm-Age scores measured in midlife are associated with higher odds of frailty and its components in late life. Methods: DNAm was measured at visit 2 or 3 in leukocyte DNA from 812 African American (AA) and 400 European American (EA) participants (mean age=54 years in AA, 57 years in EA), and was used to calculate three different DNAm-Age scores (Horvath, Hannum, and PhenoAge). Frailty status was assessed at visit 5, and dichotomized (frail/pre-frail or robust) using the following component criteria: slow walking speed, low grip strength, weight loss, low physical activity, and exhaustion. Logistic regression tested the associations of DNAm-Age scores, as the predictors of frailty status or each frailty component. Model 1 adjusted for visit 2 or 3 age, sex, education, white blood cell count, cell type proportions, and technical variables and model 2 additionally adjusted for BMI, smoking, alcohol, and visit 5 CHD, stroke, hypertension, and T2D. Inverse probability weights accounted for cohort attrition prior to frailty assessment. The Bonferroni-corrected threshold for statistical significance was set to p<8.3E-3 (0.05/6). Results: In African American participants, a 4-year increase in the PhenoAge score in midlife was associated with frailty in late life (OR=1.21, 95% CI=1.09, 1.35, p=3E-4) in model 1, which was attenuated in model 2 (OR=1.13, 95% CI=1.02, 1.26, p=2.4E-2), and with physical activity (model 2 OR=1.32, 95% CI=1.13-1.53, p=4E-4); a 4-year increase in the Hannum score was associated with the exhaustion and grip strength components (OR=1.33, 95% CI=1.13-1.57, p=6E-4; OR=1.38, 95% CI=1.16-1.64, p=3E-4, respectively). In European American participants, the DNAm-Age scores were not associated with frailty however a 4-year increase in both the Horvath and Hannum scores was associated with the weight loss component (model 2 OR=1.56, 95% CI=1.20-2.02, p=9E-4; OR=2.37, 95% CI=1.49-3.76, p=2E-4), respectively. Conclusions: In African American ARIC participants, a higher mid-life PhenoAge score was associated with higher odds of frailty/pre-frailty in late life, consistent with accelerated biological aging, but was not significant after further adjustment. The Horvath, Hannum, and PhenoAge scores were associated with some frailty components in African American and European American ARIC participants, consistent with accelerated biological aging. Following replication, future studies should examine the causal relationship between DNAm-Age, frailty, and frailty components.

Age-Related Macular Degeneration in Chronic Kidney Disease: A Meta-Analysis of Observational Studies

2018 ◽  
Vol 48 (4) ◽  
pp. 278-291 ◽  
Author(s):  
Yi-Ju Chen ◽  
Ling Yeung ◽  
Chi-Chin Sun ◽  
Chien-Chieh Huang ◽  
Kuo-Su Chen ◽  
...  
Keyword(s):  
Chronic Kidney Disease ◽  
Kidney Disease ◽  
Macular Degeneration ◽  
Observational Studies ◽  
Meta Analysis ◽  
Positive Association ◽  
Age Related Macular Degeneration ◽  
Age Related ◽  
Statistical Heterogeneity ◽  
Risk Ratios

Background: Age-related macular degeneration (AMD) is an important cause of blindness in aged people. Chronic kidney disease (CKD) was reported to be associated with a higher risk of AMD. However, supporting evidence was inconsistent between studies. This work intends to examine whether a positive association exists between CKD and AMD by systematic review and meta-analysis. Methods: A systematic search of electronic databases (Medline, PubMed, Cochrane and EMBASE) and reference lists on June 2017. The key inclusion criteria were controlled trials that investigated the relationship between AMD and CKD. The outcome measures included risk ratios and/or occurrence rates of AMD in CKD vs. non-CKD population. Data were pooled according to the type of AMD by random effect model. Results: Twelve observational studies (3 cohorts, 2 case controls, and 7 cross-sectionals) with a total 335,601 participants were included. Eleven studies reported risk ratios and 9 reported occurrence rates. Pooled prevalence for early, advanced, and any AMD were all higher in the CKD population than in the non-CKD population. The pooled multivariate adjusted OR of CKD vs. non-CKD was 1.49 (95% CI 1.11–2.02) for early, 1.55 (95% CI 1.05–2.27) for exudative, 1.58 (95% CI 1.12–2.23) for advanced, and 1.35 (95% CI 1.05–1.73) for any AMD. However, high statistical heterogeneity and methodological diversity existed. Moreover, results were inconsistent between different study designs. Conclusions: The overall results support a positive association between CKD and AMD, although some limitations exist. Given the risk that AMD is increased in CKD, regular eye screenings for the CKD population is recommended for an early detection and intervention.

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